"Pruning of biomolecules and natural products (PBNP)": an innovative paradigm in drug discovery.

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“Pruning of biomolecules and natural products (PBNP)”: an innovative paradigm in drug discovery Surendar Reddy Bathula, Srirama Murthy Akondi, Prathama S. Mainkar* and Srivari Chandrasekhar* The source or inspiration of many marketed drugs can be traced back to natural product research. However, the chemical structure of natural products covers a wide spectrum from very simple to complex. With more complex structures it is often desirable to simplify the molecule whilst retaining the desired biological activity. This approach seeks to identify the structural unit or pharmacophore responsible for the desired activity. Such pharmacophores have been the start point for a wide range of lead

Received 28th February 2015, Accepted 29th April 2015 DOI: 10.1039/c5ob00403a www.rsc.org/obc

1.

generation and optimisation programmes using techniques such as Biology Oriented Synthesis, Diversity Oriented Synthesis, Diverted Total Synthesis, and Fragment Based Drug Discovery. This review discusses the literature precedence of simplification strategies in four areas of natural product research: proteins, polysaccharides, nucleic acids, and compounds isolated from natural product extracts, and their impact on identifying therapeutic products.

Introduction

Natural products have a well-established history in the treatment of human diseases. Traditional medicines generally use extracts of plants based on local knowledge, whereas the isolation and characterisation of the active components led to the identification of drugs such as morphine (1),1 quinine (2)2 and Division of Natural Products Chemistry CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007 India. E-mail: [email protected], [email protected]

Surendar Reddy Bathula (born 1978) was educated at the Osmania University, Indian Institute of Chemical Technology (CSIR-IICT, Hyderabad, India) and UNC Chapel Hill, USA. He started as a scientist at the Central Drug Research Institute (CSIR-CDRI) in 2009 and moved in 2014 to the CSIR-IICT. He has co-authored over 20 publications and holds 4 patents. He has been awarded the Director Surendar Reddy Bathula special appreciation award for publishing best papers in 2005 from IICT. His research interests include organic synthesis and siRNA delivery using novel lipids.

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penicillin (3)3 from natural resources (Fig. 1). With the development of synthetic organic chemistry, a new era in drug discovery emerged. Although many compounds such as sulfa drugs4 (4a,b,c, Fig. 1) were synthetically derived and others such as esomeprazole5 (5), aripiprazole6 (6), rosuvastatin7 (7), duloxetine8 (8) olanzapine9 (9) and gleevec10 (10, Fig. 1) have been very successful, semi synthetic natural products such as fluticasone11 (11), a corticosteroid, also share significant success (Fig. 2). Some synthetic drugs have a planar structure containing aromatic rings and a conceptual understanding of their activity indicates binding to more than one site in the

Akondi Srirama Murthy obtained his M. Sc degree in organic chemistry from Andhra University, Visakhapatnam, India. Currently, he is working at CSIRIICT for his PhD under the guidance of Dr S. Chandrasekhar on the total synthesis of eribulin.

Srirama Murthy Akondi

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Fig. 2 Fig. 1

Natural products as drug molecules.

Early natural products and some synthetic drug molecules.

Prathama S. Mainkar

Org. Biomol. Chem.

Prathama Satyendra Mainkar was born in Indore, India in 1964. She received all her primary education in Hyderabad, India. After receiving her PhD from IICT and Osmania University under the supervision of Dr M. K. Gurjar, she worked in the pharmaceutical industry on various aspects of drug discovery. At present she is involved in HIT identification and early drug discovery for TB and CNS related diseases at CSIR-IICT.

Srivari Chandrasekhar was born in 1964 in Hyderabad, India. He obtained all his primary education in Hyderabad. After obtaining a Ph.D. under the supervision of Dr A. V. Ramarao at IICT, he moved to the University of Texas Southwestern Medical School for a postdoctoral study with Prof. J.R. Falck. He is an Alexander von Humboldt fellow. His research interests include synthesis of marine Srivari Chandrasekhar natural products, and new solvent media for organic synthesis. He is a fellow of Indian National Science Academy, Indian Academy of Sciences, National Academy of Sciences and is a recipient of the Infosys Prize 2014 for Physical Sciences, CNR Rao National Prize for Chemical Research, NASI-Reliance Industries Platinum Jubilee Award and Ranbaxy Research Award. Currently he heads the Division of Natural Products Chemistry at CSIR-IICT.


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target protein. The binding to more than one site can sometimes lead to severe side effects. Due to the unwarranted side effects of some of the marketed drugs, stringent guidelines have been established by FDA and other drug approving authorities. This prompted researchers to investigate the drug discovery process with a better rationale. A better understanding of living systems (DNA/RNA, protein folding and enzyme targets) prompted researchers to explore natural products as potential drug molecules. By virtue of their inherent chirality, 3D structure and more sp3 character, these classes of molecules are proposed to have selective binding to target proteins thus avoiding side effects. Advanced scientific methods for isolation and structure elucidation helped identify complex scaffolds such as FK-506 12 (12), cyclosporin13 (13), paclitaxel14 (14), camptothecin15 (15), galantamine16 (16), ecteinascidin17 (17), cephalotaxine18 (18) etc. (Fig. 2) with better biological activity. The experience gained by synthetic organic chemists, over the generations, has given them the confidence to attempt and synthesize such complex natural products for structure elucidation and biological evaluation. Several strategies have been employed for obtaining novel scaffolds during the total synthesis of complex natural products. Noteworthy among them are Retrosynthetic Analysis19 for identification of appropriate intermediates/starting materials; Diversity Oriented Synthesis20 for generation of library of structurally diverse compounds; Biology Oriented Synthesis21 for identification of scaffolds for the selected biological targets; synthesis of Hybrid Natural Products22,23 to create new scaffolds by combination of two natural products; Quantitative Structure–Activity Relationship;24 Fragment Based Drug Discovery25 and Diverted Total Synthesis26 with an aim to study mechanistic aspects of their biological activities (Fig. 3). Choosing starting materials from easily accessible natural products, the so called ‘chiral pool’, and their conversion to complex, stereo-chemically pure scaffolds has been a

Fig. 3 Timelines of synthetic strategies introduced by academic scientists.


Review

strategy adopted by chemists. Preferred starting materials are carbohydrate monosaccharides,27 terpenoids28 and amino acids.29 The choice of any one of them by synthetic organic chemists depends on the target molecule and number of steps required for its synthesis. With identification of newer biological targets and appropriate biological assays the fine tuning of pharmacophores and biomolecules, including biopolymers, has been a prudent and challenging exercise in creating newer structural motifs. Pharmacophores are defined as the essential features of one or more molecules which show similar biological activity. Furthermore, the identification of pharmacophores has given better molecules and plays a crucial role in expanding functionalities in drug discovery. The concept of pharmacophores, first introduced in 1909, was defined as “a molecular framework that carries ( phoros) the essential features responsible for a drug’s ( pharmacon) biological activity”.30 Computer programs are now used to find the group of atoms responsible for a drug’s action, hydrogen donors and acceptors, positively and negatively charged groups and hydrophobic regions which are the main criteria considered for determining similarities. Pharmacophore based approaches are used extensively in virtual screening, de novo design, lead optimisation and multitarget drug design.31 One of the typical examples of identifying a pharmacophore, as per classical definition, is the development of opioid alkaloids. Morphine (1) has been used traditionally as a painkiller but its addiction has also been well reported. Chemists started working on the structure of morphine to identify the pharmacophore which will have properties as a painkiller but without associated side effects such as addictive properties and respiratory depression. Thus pentazocine32 (19, Fig. 4) a synthetic narcotic, was identified and has been used to treat moderate to severe pain. However, it has similar side effects to morphine and may invoke psychomimetic effects. Other modifications in the skeleton led to compounds such as cyclazocine33 (20) and volazocine34 (21). In these derivatives the side effects were still evident and were more pronounced for volazocine and hence it was never marketed. Further trimming of the molecule led to meperidine35 ( pethidine, 22) which was assumed to be a safer drug carrying a lower risk of addiction. Detailed studies led to the obser-

Fig. 4

Morphine-inspired drugs through pruning.

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vations that none of the side effects was eliminated and its metabolite, norpethidine is known to have serotonergic effects. These pruning efforts led to more efficient synthesis of the pharmacophore. Thus, typically morphine (1) required 21 synthetic steps, pentazocine (16) could be synthesized in 1/3rd the number of steps and pethidine (19) can be achieved in 2 synthetic steps. Although the identification of a minimal pharmacophore has led to more efficient synthesis, in the case just discussed it has not been successful in a corresponding reduction in side effect liabilities. However, this experience has not deterred medicinal chemists to apply similar approaches in other areas of research. A detailed understanding of biological reactions in living systems opened a new window for finding new macromolecules as therapeutics. Monoclonal antibodies, proteins/ enzymes/peptides and saccharides are some such examples. Several attempts at finding antivirals led to the identification of nucleosides and eventually antisense nucleosides which proved to be effective against viral infections. Synthesis of known biological substances such as peptides, proteins, enzymes; antibodies, oligonucleotides and their use as medicines is a well established branch of science. Development of resistance to antimicrobials is a major health concern. To overcome the problem of resistance and/or mutations in the infection causing vectors, the pruning of macromolecules has been investigated. For example peptides have been modified using isostere peptide-bond equivalents and unnatural amino acids (for example β-, γ-, δ-amino acids); polysaccharides are pruned by substituting with unnatural sugars, converting hydroxyl groups into unusual esters and nucleic acids are pruned giving rise to antisense nucleotides. Organic chemists engaged in interdisciplinary fields have also learned the art of pruning, albeit practicing it occasionally.

2. Pruning of biopolymers and natural products Truncation and pruning of biopolymers and natural products has been followed for several decades with increased prominence in the recent past. Both the terms are used by chemists, including us, as synonyms substituting one for the other frequently. We wish to highlight the subtle differences in these two terms in this review. As per definition truncation is to shorten from the ends, typically represented by removing side chains in natural products; pruning is the removal of the unwanted parts and preferably substituting with more preferred functionalities and thereby modifying the natural product in the process. This review will present some of the successful examples of pruning with relevance to drug discovery. For a better understanding the review has been subdivided into the following four categories: 1. Pruning of proteins 2. Pruning of polysaccharides 3. Pruning of nucleic acids 4. Pruning of natural products

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2.1.

Pruning of proteins

Natural proteins, peptides and enzymes are produced in living systems and deficiency or malfunctioning of these may result in illnesses in humans. Synthetic or artificial proteins, peptides and enzymes can be administered as medicines. Bioavailability of these has been limited due to the natural degradation of peptide bonds. Researchers in this area of medicine have attempted to mimic polypeptides by incorporating amide bond surrogates36 and pruning them into smaller subunits for better efficacy. Peptides containing amide bond surrogates, as a platform technology, have been used to find better alternatives for this class of molecules. An understanding of protein folding ( primary, secondary and tertiary structures, Fig. 5) through advanced analytical tools has prompted the design and synthesis of better therapeutics. Preptin37 (23), a 34-amino acid residue peptide hormone is co-secreted with insulin from the β-pancreatic cells and is active in fuel metabolism. A shorter fragment of preptin, namely preptin-(1–16)38 (24), stimulates bone growth by proliferation and increases the survival rate of osteoblasts. However, 16 amino-acid peptide is still not an ideal therapeutic agent and it is encouraging that a shorter 8-amino acid preptin (1–8) fragment which retains an anabolic effect on the proliferation of primary rat osteoblasts with enhanced bone nodule formation has been identified. Preptin (1–8) (25) is a useful lead compound for the development of orally active therapeutic agents for the treatment of osteoporosis39 (Fig. 6). Neuropeptide Y (NPY)40 is an amidated peptide of 36 amino acids and is known to regulate physiological functions, such as food intake, learning behaviour, vasoconstriction and neuro-transmitter release.41 In addition to these functions, NPY has been recently reported to have activity against Cryptococcus neoformans, Candida albicans and Arthroderma simii. The fungicidal activity of NPY against Candida albicans, was enhanced significantly by pruning of amino acid residues at the N-terminus. The most active peptides (MICs ∼ 1 μM) were about 10-fold more potent than the intact NPY (MIC ∼ 10 μM)42 (Fig. 7).

Fig. 5

Protein structures.


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Fig. 6 Preptin and its pruned products show analogous biological activities.

Fig. 7 Neuropeptide Y structure reproduced from PDB ‘1ron’ using PyMOL software.

H2 relaxin43 is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways.44 It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises of 53 amino acids and is characterized by two separate polypeptide chains (A–B) that are cross-linked by three disulfide bonds.45 A critical active core with 38 amino acids shows similar antifibrotic activity as native H2 relaxin46 when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics47 (Fig. 8). Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism, and reward.48,49 The development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. Pruning studies have led to Orexin A

Fig. 8

H2 relaxin structure is reproduced from PDB ‘6rlx’ using PyMOL.


Fig. 9

Amino acid sequence of peptides Orexin A and B.

(26) and B (27, Fig. 9), two neuropeptides which bind to two G-protein coupled receptors (GPCRs) Orexin1 (OX1) and Orexin2 (OX2), respectively. OrexinA (26), the shortest active peptide known to date, has a 23-fold selectivity for OX1 over OX2 whereas OX2 is activated by both peptides nonselectively.50 Insulin, a peptide derived hormone, was discovered in 1921.51a After primary sequence determination in 1954,51b chemical syntheses were attempted. Initially insulin available in the market was animal based, viz., porcine or bovine. With advances in biotechnology, it is being produced from genetically modified yeast or bacteria. Even though insulin obtained from yeast or bacteria is a perfect copy of the human insulin and can be produced in copious amounts, researchers are still exploring analogues to find solutions to some of the inherent issues associated with it. Insulin, being a peptide is a difficult drug to use, especially in chronic care. It has a narrow therapeutic index, inconsistent degree of effect, is administered by injection, has low physical stability, and limited potency. Decades of research for finding a better analogue of insulin have resulted in long-acting formulations such as NPH, PEGylated, deglude, detemir, glargine insulins and fast-acting animal, lispro, aspart, glulisine insulins. Pulmonary, nasal and oral modes of administration are in clinical trials in addition to the injectable insulin which is the most common one.52 Attempts to simplify the synthesis and increase efficiency have resulted in identifying the essential amino acids for activity and the ones that can be substituted or modified. Insulin, a 51 amino acid peptide has A1–20 and B1–31 chains52 (Fig. 10). Any pruning or truncation of the chain-A set of amino acids (N terminal) resulted in a decrease in activity. However desB20–30, desB27–30 and desB26–30 had nearly the

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Fig. 11 Fig. 10

Somatostatin-14 and pruned analogues.

Amino acid sequence of human insulin chains A and B.

same activity as normal insulin in the mouse convulsion assay. The B26 position showed tolerance to stereochemical modification and replacement with D-amino acids reported higher than wild type binding affinity.53 The two peptide chains in insulin are held together by interchain sulphide bonds between CysA-B7 and CysA20-B19. Substitution of the sulphide bond between A7–B7 with 1,4-disubstituted-1,2,3-triazoles resulted in an unfolded analogue of insulin (required for glucose metabolism) but they were inactive in vivo.54 Another analogue containing a triazole moiety was designed to mimic the conformation seen in high affinity analogues such as [N-Me-tyr B26]-insulin by fixing the B26 turn-like conformation by chemically cross-linking the amino acid from the B20–B30 region. Cyclo[GFFY-Pent(N3)P-G-Prg]-insulin showed a higher binding affinity (101.5%).55 The tetradecapeptide somatostatin (28, SRIF14; somatotropin release inhibitory factor) is reported to be a negative regulator of a variety of hormones. In particular, SRIF14 acts as a potent inhibitor of growth hormone from the anterior pituitary and also inhibits the secretion of glucagon and insulin. When compared to its broad spectrum of biological actions, it has little therapeutic value due to the short (2–3 min) in vivo half life.56 Extensive structure–activity studies on somatostatin led to the identification of the tetrapeptide unit Phe7Trp8Lys9Thr10 (superscript numbers indicate the sequence of SRIF14) as the pharmacophore is essential for biological activity. Further peptidomimetic and peptide modifications resulted in the development of clinically useful pruned analogues i.e. the cyclic octapeptide, octreotide (29, Sandostatin®, half life 2 h) and cyclic Veber–Hirschmann hexapeptide L363,301 (30, Fig. 11). Octreotide is an approved drug for the treatment of acromegaly, diarrhea due to VIPoma and carcinoid syndrome. Furthermore it is used as a source for the development of various radiopharmaceuticals such as Octreoscan® and OctreoTher® for the diagnosis and peptide receptor radionuclide therapy of tumors, respectively.57 The use of peptides as drugs is increasing with more understanding of the targets as well as binding sites but there are

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still some limitations in developing peptides. The low bioavailability (generally administered as injections), short half-life due to rapid degradation, fast removal from circulation by the liver or kidney, poor ability to cross physiological barriers due to their hydrophilic nature, high conformational flexibility leading to lack of selectivity, activation of several targets leading to side effects, risk of immunogenic effects and high synthetic and production costs all act as deterrents and need to be addressed in pursuit of finding better therapies. Currently there are about 140 peptide based drug candidates in clinical trials. Some examples of marketed products or those in clinical trials are presented in Table 1; the selection is based on pruned peptides.58,59 2.2.

Pruning of polysaccharides

Polysaccharides are abundant, stable, safe, non toxic, hydrophilic and biodegradable natural polymers made up of carbohydrate monomeric units and are found in a wide variety of species including algae, plants, microbes, and animals.60 These polymers have a variety of biochemical and biomechanical functions in nature and also act as templates for biomimetic biomaterials.61 Polysaccharide functions are highly dependent on their structures as well as molecular weights. In most cases low molecular weight polysaccharides exhibit better biological activities over their parent molecules62 as high molecular weight polysaccharides have limited cell permeability. For example low molecular weight fucan showed better antiproliferative activity in smooth muscle cells than their high molecular weight polymers.63 The minimum number of saccharide units necessary to perform the biological activity of fucan is about 30. Heparin (31) and its fragments [fondaparinux, 32 and low molecular weight heparin (LMWH) 33] are widely used anticoagulants for the prevention of venous thromboembolism. Fondaparinux (32, Arixtra®) (Fig. 12) is a structurally simplified heparin derivative which binds to antithrombin (AT) III. It is a synthetic pentasaccharide and is distinct from LMWH and heparin. Fondaparinux (32) consists of a minimal sequence of


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Table 1

Review

Pruned peptide drugs in clinical trials/market

INNa

Brand names

Companies

Indications

Comments

Bivalirudintrifluoroacetate hydrate Epitifibatide

Angiomax, Angiox

Ceruletidediethylamine

Takus, Tymtran

Goserelin acetate Leuprolide acetate or Leuprorelin Nafarelin acetate

Zoladex Eligrad, Enatone, Lucrin, Depot, Lupron, Prostap, Viadur Synarel, Synrelina

AstraZeneca Abbott, Astellas Pharma, Bayer, Genzyme, J&J, Takeda etc. Pfizer, Searle

Anticoagulant in patients with unstable angina undergoing PTCA or PCI Acute coronary syndrome, unstable angina undergoing PCI Diagnosis of the functional state of the gall-bladder and pancreas and stimulant of the gastric secretion Advanced prostate cancer, breast cancer Advanced prostate cancer, breast cancer, central precocious puberty

In market

Intergrillin

Nycomed Pharma, The Medicines Company Millennium Pharma, GSK, Schering–Plough Pharmacia and Upjohn, Farmitalia Carlo Erba

Abarelix acetate

Plenaxis

Desmopressin acetate

DDAVP, Defrin, Minirin, Minirinmelt, Octim, Stimate

Precis Pharma, Specialty European Pharma Apotex, Bausch & Lomb Pharma, Behring, SaofiAventis, Teva

a

In market In market In market In market

Central precocious puberty, endometriosis, uterine fibroids, ovarian stimulation in in vitro fecundation Advanced prostate cancer

In market

Central diabetes, insipidus, nocturnal enuresis, nocturia and stoppage of bleeding or haemorrhage in haemophilia A patients

In market

In market

Examples are based on pruning where the natural peptide is modified by inclusion of a non-natural amino acid or other scaffold.

Fig. 12 Structures of heparin, low molecular weight heparin and Fondaparinux (Arixtra®).

heparin able to activate AT III to produce the inhibition of factor Xa. Unlike heparin it is a homogeneous low molecular weight polymer of 1728 Da and inhibits thrombin generation by inhibiting only factor Xa activity via binding to AT. It does not possess other actions of heparin such as inhibition of thrombin and release of TFPI (tissue factor pathway inhibitor). Low AT levels can limit the efficacy of fondaparinux.64 Fondaparinux is a US FDA and the European CPMP approved drug


for the prophylaxis of deep venous thrombosis in patients undergoing surgery for bone joint replacement. LMWH and Fondaparinux are better drugs than heparins in terms of their bioavailability, non-specific binding to plasma proteins and unpredictable dose response. The half-life of heparin is 45 min compared to LMWH which has a 4–5 h half-life and Fondaparinux which has a 17–21 h half-life. Chitosan, deacetylated chitin, is the most abundant biopolymer after cellulose, accessible from marine crustaceans, shrimp and crabs.65 Chitosan (31) is a biodegradable, nontoxic and non-allergenic polymer. It is neither soluble in aqueous solutions nor in organic solvents and the degree of deacetylation on the D-glucosamine repeat unit affects its solubility.66 Low molecular weight chitosan (LMWC) and chitooligosaccharides (COS) are widely used in agriculture, textiles, pharmaceuticals and environmental fields and exhibit interesting activities such as immunity regulation, anti-tumour, liver protection, blood lipids lowering, anti-diabetic, antioxidant and anti-obesity activities in human health. These are also used to prepare biocompatible materials for biomedical applications including hydrogels, films, fibres and sponges.66–69 Type 2 diabetes accounts for 90–95% of all diagnosed cases in adults. Dietary carbohydrates are hydrolysed by pancreatic α-amylase followed by α-glucosidase which releases the sugar in blood. LMWC generated through enzymatic digestion of chitosan are known to prevent progression of diabetes in streptozotocin induced diabetic mice.70a,71 They act through α-glucosidase inhibitory activity. GO2AK1 (32, Fig. 13) is one such LMWC with molecular weight ∼1000 Da. It has a dual effect towards glucose management: (1) inhibition of carbohydrate hydrolysing enzymes and (2) aiding glucose absorption in muscle and fat cells. These are facilitated by its significant absorption in the blood. At present GO2AK is in Phase II trials.70b,71

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Fig. 13


Structures of chitosan and GO2AK1.

Naturally occurring complex carbohydrates such as inulins, glucans, dextrans, lentinans, glucomannans and galactomannans can potentiate antigen mediated immune response.72 QS-21 is an emerging complex carbohydrate based natural product immuno-adjuvant (molecules used to enhance the immunological responses associated with vaccines) used in several prophylactic and therapeutic vaccine clinical trials for the prevention as well as treatment for malaria,72 HIV, hepatitis, tuberculosis, Alzheimer’s disease and cancer. Originally it was isolated from a purified saponin fraction of Quillaja saponaria (QS) tree bark. QS-21 has two different isomers QS-21-Api (36a, Fig. 14) and QS-21-Xyl (36b) which comprise of

Fig. 14

Development of the minimal structural analogue of QS-21.

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three different class of organic compounds: a triterpene, a branched trisaccharide, and a glycosylated pseudodimeric acyl chain.73 Along with the promising adjuvant activity, QS-21 has major drawbacks related to bio-availability, toxicity and stability at physiological pH. To fully utilize the potential of QS-21 as a vaccine adjuvant researchers have developed a simpler, stable synthetic derivative QS-21 (SQS). To improve synthetic accessibility, the acyl-chain domain variants of QS-21 were replaced with stable amide linkages and the linear tetrasaccharide domain was reduced to the trisaccharide variant.73–75 However, these modifications did not reduce the toxicity of the target adjuvant. A recent report76 described the minimal structural unit of QS-21 which decouples adjuvant activity from toxicity via pruning of the target compound. Through structure–activity relationship (SAR) studies it was identified that the entire branched trisaccharide domain and the C4aldehyde substituent of QS-21 are not required for adjuvant activity and QS-21 was pruned accordingly to obtain 37. Immunity augmenting materials, known as Biological Response Modifiers (BRM), are used to treat cancer. Proleukin®, Intron®, Roferon-A®, Aldara® and Revlimid® are commonly used BRMs in cancer therapy.77 α-Galactosylceramide (α-Gal-Cer, KRN7000, 38, Fig. 15) is an upcoming BMR which activates natural killer T (NKT) cells in vivo and initiates the production of several cytokines including interferon (IFN)-γ, interleukin (IL)-4, and IL-17 and thereby influence other immune cells.78 CD1d (cluster of differentiation 1 family of glycoproteins) expressed on antigen presenting cells plays an important role in the recognition of GalCer by NKT cells. Structurally simple analogues, 39 and 40 of GalCer with a similar magnitude of activity in modulating immune response have recently been reported79 which highlight the success of pruning strategies. These reports clearly demonstrate the importance of structurally simplified polysaccharides i.e. low molecular weight polysaccharides in future medicine and diagnostics. Along with the advancement in carbohydrate chemistry and structure determination techniques, structure simplification by pruning facilitates the discovery of low molecular weight polysaccharide for the exigent diseases. Several groups are working towards

Fig. 15 KRN7000 and pruned analogues which have a simplified structure but the same magnitude of activity.


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Organic & Biomolecular Chemistry Table 2

Low molecular weight polysaccharide drugs and active molecules which are under development

Clinical phasea

Company

Drug

Target

Disease

GlaxoSmith Kline

Fondaparinux (Arixtra®)

Factor Xa

Anticoagulation

Sanofi

Enoxaparin (Lovenox®, Xaparin® and Clexane®) KRN7000

Antithrombin III

Deep vein thrombosis

Immune system stimulation Immune system stimulation Immune system stimulation Glucose levels

Lung cancer Meningococcal disease HER2-positive breast cancer Type 2 diabetes

Phase 3

Immune system stimulation

Prostate cancer

Phase 2

European Organisation for Research and Treatment of Cancer – EORTC Hualan Biological Engineering, Inc.


Review

National Cancer Institute (NCI) Yonsei University Memorial Sloan-Kettering Cancer Center a

ACYW135 Meningococcal polysaccharide vaccine Polysaccharide-K + trastuzumab GO2KA1 (low molecular weight chitosan oligosaccharide) QS21: immunological adjuvant

Marketed drug Marketed drug Phase 1

Phase 2 Phase 2

Source: Clinicaltrials.gov.in.

finding a better polysaccharide-based drug and Table 2 enlists some of the compounds under development.

2.3.

Pruning of nucleic acids

Detailed studies on transcription and translation identified the phenomenon where the primary RNA transcript undergoes structural reorganization, i.e., the removal of intronic sequences, to yield a mature mRNA that is considerably smaller with an average size of 1–3 kb than the first RNA transcript.80,81 The process of removing the intronic sequences is called RNA splicing. Recent development in this area of research describes the identification of a new class of small RNAs including microRNAs which modulate the gene expression by acting as naturally occurring antisense oligonucleotides.82 These small RNAs are the products of large RNAs generated by a natural pruning process (Fig. 16). The ‘antisense’ and siRNA research is based on the concept of pruning. The phenomenon of nucleic acid (RNA) mediated gene silencing was originally observed in transgenic petunia plants in the early 1990s.83 “Homology-dependent gene silencing” (HDGS)84 was discovered by injection of long double stranded RNA (dsRNA) into the nematode, Caenorhabditis elegans, which induced potent silencing of target mRNAs.85,86 RNA interference (RNAi)87 which works through small interfering RNAs (siRNA)88–91 is being explored as a new category of treatments for genetic diseases, viral diseases and cancer. Proteins that cannot be targeted by conventional small molecule drugs are particularly attractive targets for RNA-based drugs. These polyanionic molecules need a vector (transfection agent) for their intracellular entry and delivery vectors determine the clinical success of most of the RNA based drugs. The advances in antisense and siRNA therapy paved the way to discover drugs especially in the unmet sector. Noteworthy examples of the therapeutic areas, class of molecules and their status are given in Table 3.


Fig. 16

Nature synthesizes small RNA drugs via pruning of long RNAs.

There are still ample challenges in the small RNA sequences to be identified as potential therapeutics in healthcare. With the advancements in genome sequencing,92 automation in chemical synthesis to design and produce artificial sequences93 at will, advanced crystallography and characterization with mass spectra,94 it is not a distant dream that the ever demanding health care will be provided by research in this area and will provide complementarity to small molecule based drugs. 2.4.

Pruning of natural products

A natural product in the field of organic chemistry is usually restricted to purified organic compounds isolated from natural sources. Natural products are produced by the pathways of primary and secondary metabolism whereas in a broader sense it is any compound produced by a living organism. In the parlance of medicinal chemistry, a natural product is a secondary metabolite, which is not essential for the survival of

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Table 3

Organic & Biomolecular Chemistry Pruned nucleic acids in clinical trials

Company

Drug

Target

Disease

Clinical phasea

Santaris Pharma A/S

miR-122

Hepatitis C

Phase II

Sterna Biologicals GmbH & Co. KG Sarepta Therapeutics, Inc.

SPC3649 (antisense oligonucleotide) SB010 (antisense oligonucleotide) AVI-7100

GATA-3 mRNA

Asthma

Phase II

Influenza

Phase I

INSYS Therapeutics Inc Isis Pharmaceuticals Quark Pharmaceuticals

LErafAON ISIS 104838 QPI-1007 (siRNA)

M1 and M2 genes of influenza A virus. Raf gene/Raf-1 protein TNF-alpha Caspase 2

Phase I Phase II Phase I

Quark Pharmaceuticals Silence Therapeutics GmbH

I5NP (siRNA) Atu027 (siRNA)

p53 PKN3

Neoplasms Rheumatoid arthritis Non-arteritic anterior ischemic optic neuropathy Acute renal failure Advanced solid tumours

a

Phase I Phase 1

Source: Clinicaltrials.gov.in.

the organism but nevertheless provides it an evolutionary advantage. Natural products can be classified into three main categories: (a) Primary metabolites: these are found in all cells and are necessary for the survival of the cells and include amino acids, carbohydrates, lipids, nucleic acids etc. (b) Polymeric organic materials: these form the structure of cells and include cellulose, lignins and proteins. (c) Secondary metabolites: these are unique organic compounds that are produced by species and have been optimized through evolution for use as ‘chemical warfare agents’ against prey, predator and competing organisms. Each species has its own niche secondary metabolite, depending on its environment. Secondary metabolites mainly exert their activity through interactions with specific targets and this is used to identify a drug molecule. From the early history natural products have been used in health care and prevention of diseases and it has been recorded in the ancient civilizations of the Indians, Chinese, and North Africans. Nature produces chemically diverse and structurally complex molecules using biosynthetic pathways. Many natural products are cytotoxic and have been selected and optimized through evolution for use as chemical defense against predation, mediation of spatial competition, prevention of fouling, facilitation of reproduction, protection against UV radiation and chemical signalling to ensure survival. The use of natural products as pharmaceutical drugs, nutritional supplements, cosmetics and agrochemicals is well documented.95 Natural products have been the excellent starting point in drug discovery owing to their ability to selectively bind to the target proteins. Understanding the structural requirements of an individual natural product for its biological evaluation is very crucial. Recent literature exemplifies the importance of structural pruning of complex natural products in order to generate a prototype structure for drug discovery. Molecular pruning of natural products is a purposeful process in modern

Org. Biomol. Chem.

Table 4 Examples of pruning of natural products

S. no.

Parent molecule

Pruned molecule

Reference

1. 2. 3. 4. 6. 7. 8.

Halichondrin Migrastatin Bryostatin Macfarlandin E Anguinomycin D Farinosone C Jaspine B

Eribulin Migrastatin core analogue Bryostatin analogue Macfarlandin E analogue Anguinomycin D analogue L-Tyrosinol amide Pruned analogue

97 121 122 123 124 125 126,127

drug discovery that involves the replacement or reduction of the unwanted appendages of natural products whilst retaining critical functionalities for biological activity. It is an emerging process for molecular editing of complex natural products. This strategy also provides opportunities for structural simplification and chemical modification of complex natural products. The simplified analogues and/or new chemotypes are then screened against a given pharmacological target to elucidate their mechanism of action. An excellent review by J.-Y. Wach and K. Gademann96 describes the latest trends in the simplification of complex natural products. It highlights the advantage and requirement of molecular pruning in identifying effective drug molecules (Table 4). This section excludes work covered therein. One of the most discussed examples, in the literature, of pruning has been the development of eribulin from marine toxin, halichondrin (41, Fig. 17) by Eisai Pharma in collaboration with Kishi et al.97 Eribulin (42) is used for treating cancers which show resistance to other anticancer drugs. Myriocin (43, Fig. 18) a potent immunosuppressive natural product, was isolated from a culture broth of Isaria sinclairii described in a traditional Chinese medicine.98 It inhibited proliferation of T cells in mouse allogeneic mixed lymphocyte reaction by culturing BALB/c mouse spleen cells with mitomycin C-pre-treated C57BL/6 mouse spleen cells as stimulator cells in vitro. However a higher dose of myriocin induced


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Review

Fig. 20

Pruning of spicamycin to KRN5500.

strong toxicity in vivo. Based on the SAR studies the molecule was pruned to get fingolimod 99 (44). Fingolimid showed more potent immunosuppressive activity with reduced toxicity and improved physicochemical properties in vivo. It is an immunomodulatory drug approved in 2010 by FDA to reduce relapse and delay disability progression in patients with the relapsing form of multiple sclerosis. Phlorizin (45, Fig. 19) a phytochemical belonging to the class of polyphenols, occurs in the bark of pear, cherry, apple

and other fruit trees.100 It is sweet in taste and is a competitive inhibitor of SGLT1 and SGLT2 (sodium-glucose transport protein subtypes 1 and 2) as it competes with glucose for binding to the carrier, which reduces renal glucose transport thereby lowering blood glucose levels. Pruning of phlorizin led to the synthetic analogue, dapagliflozin101 (46) used to treat type 2 diabetes. It inhibits SGLT2 responsible for reabsorption of glucose in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through urine. Dapagliflozin has been approved by FDA in 2014 for glycemic control along with diet and exercise for type 2 diabetes. The nucleoside like anti-neoplastic antibiotic, spicamycin (47, Fig. 20) was originally isolated from the bacterium Streptomyces alanosinicus.102 It showed in vivo antitumor activity against several human tumours, especially high activity was detected against SC-9, human gastric cancer. The length of the side chain influenced the in vitro cytotoxicity and in vivo toxicity of the molecules with more toxicity associated with longer chains. To solve the toxicity issues semi-synthetic derivatives were investigated and one of them, KRN5500 103 (48) has been approved by FDA as a ‘Fast Track Drug’ for two separate orphan designations, viz., for the treatment of multiple myeloma and parenteral treatment of painful chronic chemotherapy-induced peripheral neuropathy. KRN5500 inhibits protein synthesis by interfering with endoplasmic reticulum and Golgi apparatus functions and induces cell differentiation and caspase-dependent apoptosis for myeloid leukemia cells. Ouabain or g-strophanthin (49, Fig. 21) is a cardiac glucoside found in the ripe seeds of the African plant Strophanthus

Fig. 19

Fig. 21

Fig. 17

Pruning of halichondrin to eribulin.

Fig. 18

Pruning of myriocin to fingolimod.

Pruning of phlorizin to dapagliflozin.


Pruning of ouabain to rostafuroxin.

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Fig. 22


Pruning of staurosporine to sotrastaurin. Fig. 24

Fig. 23

FK506 and 506BD.

gratus and in the bark of Acokanthera ouabaio.104 It is sometimes used for the treatment of heart conditions and also as an arrow poison by some of the tribes. The classical mechanism of ouabain activity involves inhibition of plasma membrane Na+/K+-ATPase through binding to it at higher concentrations attainable in vivo with intravenous dosage. Rostafuroxin105 (50) is an antihypertensive agent in Phase IIb clinical trials which displaces ouabain binding from kidney Na+–K+ ATPase without interfering with other receptors or enzymatic activities known to be involved in the blood pressure regulation or hormonal steroid control. The antihypertensive activity of rostafuroxin is long-lasting and is devoid of any digitalis-like cardiac effects. Staurosporin (51, Fig. 22) is a natural product originally isolated from Streptomyces staurosporeus.106 It has a wide range of biological activities including antifungal to antihypertensive. It inhibits protein kinases through competing prevention of ATP binding with high affinity. It binds to many kinases and hence has very little selectivity. A structural modification through pruning led to sotrastaurin (52) which is in Phase II clinical trials for the inhibition of solid organ allograft rejection. Sotrastaurin is a selective inhibitor of protein kinase C (PKC) isotypes and exerted an immunomodulatory effect via selective inhibition of early T cell activation.107 FK506 (12, Fig. 23) is an immunosuppressive agent isolated from Streptomyces tsukubaensis from a Japanese soil sample.12 It was approved by FDA for clinical use in 1994. Being closely related to rapamycin and exhibiting activity as cyclosporin (13), affinity studies were carried out to identify the protein

Org. Biomol. Chem.

Bryostatin 1 and its analogue.

responsible for the binding of the molecules. FK506 Binding Protein (FKBP) was identified during these studies and was shown to be present in several isomeric forms. Later it was shown that rapamycin also binds to FKBP. Based on the binding pockets of the FKBP, a pruned analogue, 506BD (53) was synthesized that preserved the binding domain of the parent molecule and the cyclic structure was designed to ensure 90° angle for optimal binding to FKBP. 506BD was shown to be a strong inhibitor of FKBP isomerase activity (Ki = 5 nM).108 Bryostatin 1 109–111 (54, Fig. 24) was isolated in 1968 from Bugula neritina, a marine bryozoan and its structure was resolved in 1982. The bryostatins inhibit the protein kinase C family of 1,2-diacyl-sn-glycerol (DAG) activated serine/threonine phosphorylase. The PKC family is involved in numerous cell-type pathways including tumour promotion. Activation of different PKC isozymes has been invoked in a number of diseases such as cancer, diabetes, heart diseases, Alzheimer’s disease etc. Bryostatin1 activates PKC but induces a limited number of effects compared to phorbol. Analogue 55 with ring expansion was synthesized and is an excellent example of pruning. The new analogue, 55, showed potent cytotoxicity against NCI ADR cells.112 Amphotericin B113 (56, Fig. 25) is an antifungal agent first isolated in 1955 from a Venezuelan strain of Streptomyces nodosus. It was rapidly introduced as a drug for its potent antifungal activity. It is also found to work against Leishmaniasis. SAR for amphotericin B has been determined by studying some semi-synthetic analogues. One such analogue, 57, has the polyene unit replaced with a diyne–diarene unit of roughly the same length. Unfortunately, this compound was devoid of any antifungal activity thus establishing the requirement of a polyene unit for the desired activity. Nevertheless this provides an example of pruning of the natural products.114 Pladienolides115,116 (58, Fig. 26) have been isolated from the fermentation broth of Streptomyces platensis Mer-1107 through a bioassay guided fractionation which inhibits hypoxia induced VEGF expression. They also inhibit splicing of pre-mRNA thereby generating an antitumor effect. E7107 (59) an analogue of pladienolide B (58) has entered clinical trials. Pruning of macrolides in our group led to analogues (60) which had activity comparable to the natural product.117


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Fig. 25

Review

Amphotericin and diarene analogue. Fig. 27

Pruned prostaglandins.

Fig. 28

Galantamine.

The compound with the basic morphine-like skeleton was synthesized in our group and screening indicated the AChE inhibitory activity to be slightly lower than the parent natural product.120 Fig. 26

Pladienolide.

3. Conclusions Prostaglandins are potent local hormone-like lipid compounds that have important functions in human body. They are autocrine and paracrine which are locally acting messenger molecules. They are produced at many places throughout the human body and their target cells are present in the immediate vicinity of the site of their secretion. These compounds are chemically unstable, rapidly metabolised and have numerous side effects. Pruning is one method followed for identification and synthesis of more stable analogues with lesser side effects (60, 61, 62, Fig. 27).118 Galantamine119 (63, Fig. 28) is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of a vascular origin. It is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs). Synthesis of an analogue of galantamine devoid of ring C (64) is a fine example of pruning.


The simplification of natural products via pruning is a useful strategy in drug discovery to identify the relevant pharmacophore for activity, selectivity and toxicity. This information has been used in conjunction with Quantitative Structure–Activity Relationship, Fragment Based Drug Discovery, Diversity Oriented Synthesis, and Biology Oriented Synthesis to facilitate drug discovery.

Acknowledgements The authors thank Mr Duncan Judd of Awridian Ltd., UK, for fruitful discussion. The authors also thank CSIR, Ministry of Science and Technology, New Delhi, for the XII Five-year Plan Project ORIGIN (CSC-0108).

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