Insights into drug discovery from natural products through structural modification.

FITOTE-03169; No of Pages 11 Fitoterapia xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Fitoterapia journal homepage: www.elsevier.com/locate/fitote

Review

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Jichao Chen, Wenlong Li, Hequan Yao, Jinyi Xu ⁎

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State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China

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Insights into drug discovery from natural products through structural modification

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Keywords: Natural products Druggability Structural modification

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Contents

Natural products (NPs) have played a key role in drug discovery and are still a prolific source of novel lead compounds or pharmacophores for medicinal chemistry. Pharmacological activity and druggability are two indispensable components advancing NPs from leads to drugs. Although naturally active substances are usually good lead compounds, most of them can hardly satisfy the demands for druggability. Hence, these structural phenotypes have to be modified and optimized to overcome existing deficiencies and shortcomings. This review illustrates druggability optimization of NPs through structural modification with some successful examples. © 2015 Published by Elsevier B.V.

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Article history: Received 5 March 2015 Accepted in revised form 19 April 2015 Accepted 20 April 2015 Available online xxxx

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Potential of natural products . . . . . . . . . . . . . . . . . 1.2. Challenges with natural product research . . . . . . . . . . . 2. General principles for structural modification of natural products . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Examples for structural modification of natural products . . . . 2.1.1. Improvement of physico-chemical properties . . . . . 2.1.2. Improvement of plasma stability . . . . . . . . . . . 2.1.3. Improvement of metabolic stability . . . . . . . . . 2.1.4. Improvement of crossing the blood–brain barrier (BBB) 2.1.5. Improvement of potency and selectivity . . . . . . . 2.1.6. Employment of prodrug strategy . . . . . . . . . . . 2.1.7. The intellectual property attainment status of NPs . . . 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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45 ⁎ Corresponding author at: State Key Laboratory of Natural Medicines, The Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Tel.: +86 25 83271299; fax: +86 25 83302827. E-mail address: [email protected] (J. Xu).

http://dx.doi.org/10.1016/j.fitote.2015.04.012 0367-326X/© 2015 Published by Elsevier B.V.

Please cite this article as: Chen J, et al, Insights into drug discovery from natural products through structural modification, Fitoterapia (2015), http://dx.doi.org/10.1016/j.fitote.2015.04.012

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J. Chen et al. / Fitoterapia xxx (2015) xxx–xxx

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Structural diversity is a striking feature of NPs accounting for their lasting importance in drug discovery [5,6]. With increasing druggable targets in the postgenomic era, chemical diversity of screening libraries plays a major role in the fierce competition among pharmaceutical companies. In this respect, NPs are a rather indispensable complement to synthetic compound collections [7,8]. NPs are also featured by steric complexity and differ from synthetic compounds with respect to the statistical distribution of functionalities [8]. They interrogate a different and wider chemical space, and possess a broader dispersion of structural and physicochemical properties than synthetic compounds [9–11]. Some academic groups and companies have made their attempts to synthesize increasingly complex structures to match the chemical space occupied by NPs, however, about 83% of core ring scaffolds present in NPs are still absent from commercially available molecules and screening libraries [12]. In addition, most NPs show more favorable ADME/T properties compared to synthetic molecules, although they often deviate from “druglikeness” criteria, such as Lipinski's Rule of Five [13,14]. Moreover, NPs recognized as ‘privileged structures’ also provide attractive scaffolds for combinatorial synthesis and library design [15–17], and serve as chemical probes for the validation of new drug targets [18].

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1.2. Challenges with natural product research

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Despite the proven track record of natural products in drug discovery and their uncontested unique structural diversity, there are still several problems associated with NPs. Typical limitations of NP leads are low solubility or chemical instability, which especially hamper the development of parenteral drugs [19]. Furthermore, many natural products are complex structures with high molecular weight. “Heavy” structures break Lipinski's rules and will most likely exhibit no absorption from the gut into the blood, therefore impeding oral formulation [20]. Additionally, the intellectual property situation is often less clear in unmodified NPs. Although naturally active substances are usually good lead compounds, most of them can hardly satisfy the demands for druggability. NP leads are

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2. General principles for structural modification of natural products

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The ultimate goal of structural modification of NPs is to obtain new drugs. Pharmacological activity and druggability are two essential factors for drug innovation. Pharmacological activity is definitely indispensable, and druggability is destined by physico-chemical, biochemical, pharmacokinetic and safety properties of drugs. Structural modification of NPs should, therefore, be involved in all the contents of the above two aspects. It is necessary to perform selective modification of NPs according to the deficiency or shortcomings of the structure, the activity, and physico-chemical and pharmacokinetic properties. Generally, the following principles should be followed: increasing potency and selectivity, improving physicochemical properties such as solubility, distribution, ionizability, etc., enhancing the chemical and metabolic stability, improving biochemical properties, improving pharmacokinetic properties including absorption, distribution, metabolism and excretion, eliminating or reducing side-effects, and attaining intellectual properties. Some successful examples of NPs through structural modification are illustrated as follows.

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1.1. Potential of natural products

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Over the past century, a number of natural compounds extracted from animals, plants, microbes and marine organisms have been used to treat human diseases [1,2]. The endeavor involved well-known drugs such as penicillin (antibacterial), morphine (analgesic), artemisinin (antimalarial) and paclitaxel (anticancer). Review of natural products (NPs) over the 30 years from 1981 to 2010 revealed that approximately 40% of the developed therapeutic agents approved by FDA were NPs, their derivatives, or synthetic mimetics related to NPs [3]. Despite increasing competition from combinatorial and classical compound libraries, there has been a steady introduction of NP-derived drugs in the last years. A total of 19 NPs-based drugs were approved for marketing worldwide between 2005 and 2010, covering infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, neurological, inflammatory and related diseases, and oncology [4].

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frequently optimized through structural modification to achieve the final candidate. Of the 58 NP drugs launched in the period of 1981–2011, 31 are structural analogues of the native NP leads [21].

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1. Introduction

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2.1. Examples for structural modification of natural products

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2.1.1. Improvement of physico-chemical properties

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2.1.1.1. Increase of low solubility. Low water solubility limits absorption and causes poor oral bioavailability. Although many cutting-edge technologies have been developed to formulate insoluble compounds over the years, medicinal chemists would like to solve drug delivery problems with “covalent bonds” [22], to improve solubility through structural modifications including adding ionizable or polar groups. Typically, a basic amine or a carboxylic acid is introduced to the structure. Artemisinin (1), a sesquiterpene lactone peroxide originally isolated from Chinese traditional medicine qinghao (Artemisia annua L.) [23], has shown potent activity in a variety of diseases, most notably malaria and, more recently, several types of cancers [24] and cytomegalovirus [25]. However, its poor solubility in water or oil caused difficulty in its rescue of severe malaria patients. To address this, oil-soluble artemether (2) and water-soluble sodium artesunate (3) were approved in China in 1987. The sodium salt of a carboxylic acid analogue achieved higher solubility, yet in this case the compound was unstable, resulting from the facile hydrolysis of the ester linkage. Although the carboxylic group in compound 4 was linked to the artemisinin nucleus via a more stable ethereal linkage, their antimalarial activity was much less active than that of sodium artesunate [26]. Ultimately, the amine analogues (maleates or oxlates of 5) attained better solubility and stability and were active after oral dosing [27]. Despite immense efforts, no new artemisinin derivative has been developed. Artemisone (6) was a 10-alkylaminoartemisinin analogue whose preparation entailed chemistry distinct to that leading to other derivatives and which extended the efficacy limit beyond

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those of the known artemisinins [28]. The drug is currently in phase III clinical trials.

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solubility (N 10 mg/mL). The compound has a water-soluble dipeptide ester group at the C-20 position of 17, which is stable at low pH but rapidly converts to the active drug 17 at physiological pH by intramolecular cyclization of the dipeptide moiety [38].

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Camptothecin (11), a pentacyclic alkaloid isolated from Camptotheca acuminata [36], acts as a potent topoisomerase I inhibitor (Top I) showing strong antitumor activity both in vitro and in vivo [37]. Yet, the clinical application of 11 as an anticancer agent was limited due to its nonmechanismrelated toxicity and an extremely poor solubility. Two strategies had been taken to circumvent this solubility issue: (i) synthesizing camptothecin analogues with an amino functional group, e.g., topotecan (12) and Dx-8951(13), and (ii) synthesizing water-soluble prodrugs of lipophilic camptothecin analogues, e.g., irinotecan (14) [38]. Both 12 and 14 have been approved for the treatment of several types of cancer patients [39]. Moreover, water-soluble quaternary salt camptothecin analogues (15) were also prepared with comparable or superior Top I inhibitory activities but lower cytotoxicities in relation to 11 [40]. Additionally, another analogue TP300 (16) exhibited a broader antitumor spectrum and more potent antitumor activity than 12 with improved

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2.1.1.2. Simplification of complex structure. NPs with complex structure often remain a challenge for their chemical synthesis, especially some of those with limited availability of source materials from which they are extracted hampered their clinical application. Furthermore, complex NPs often possess higher molecular weights and bring about poor oral absorbability. Hence, it is necessary to develop structurally simpler compounds derived from NPs while retaining their bioactivity. In this respect, Morphine (18) is particularly telling. 18 inspired the development of potent analgesics through the preparation of structurally simplified analogues such as morphinanes (19), benzomorphanes (20), phenylpiperidines (21), and the simplest one, methadone (22). Despite their decreasing complexity, analgesic activity is retained to different degrees and with different affinities for opioid receptor subtypes [41]. As such, strategies for structural simplification include decreasing the molecular size and eliminating unnecessary chiral centers.

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Oridonin (7) is a complex ent-kaurane diterpenoid extracted from the traditional Chinese herb Isodon rubescens [29]. 7 has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile [30–32], and has recently been reported to have a potent antimycobacterial activity [33]. Nevertheless, the sparing solubility (1.29 mg/mL) limited its extensive use in clinic. By introducing various water-soluble amino acids and carboxylic acids into the C-14 position of 7, 1-O- and 14-O- derivatives of oridonin were obtained with improved solubility (N50 mg/mL) and stronger cytotoxicity against six cancer cell lines (BGC-7901, SW-480, HL-60, BEL-7402, A549 and B16) than that of 7 (IC50 = 26–40 μM), especially compounds 8 and 9 with IC50 values of 0.84 μM in HL-60 cell and 1.00 μM in BEL-7402 cell, respectively [34]. Recently, synthesis of the nitrogen-enriched oridonin derivatives with thiazole-fused A-ring (10) led to potent antiproliferative effects against breast, pancreatic and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility (N40 mg/mL) [35].

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Largazole (23), a depsipeptide natural product isolated from the cyanobacterium Symploca sp. [42], is a histone deacetylase (HDAC) inhibitor with potent antiproliferative activity and selectivity for cancer cells. One study showed that C7-demethyl largazole was equipotent to 23 [43], indicating that the C7-methyl is unimportant for activity. Another study displayed that related thiazole–thiazole analogue 24 exhibited an intermediate HDAC inhibitory activity compared to largazole thiol [44], suggesting that thiazoline–thiazole moiety could be replaced with bisthiazole fragment. Based on these findings, a series of simplified analogues were developed by retaining the bisthiazole cap group while cleaving across the β-hydroxy and thiazole fragments. Among them, 25 showed a comparable HDAC inhibitory activity (IC50 = 70 nM) to that of 23 (IC50 = 13.7 nM) and was efficacious when administered orally [45].


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disease-modifying agent approved in 2010 for the treatment of 294 relapsing–remitting multiple sclerosis [58]. 295 296

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2.1.1.3. Improvement of chemical stability. Chemical instability in bioassay buffer solution reduces the compound concentration and produces decomposition products that may be active. Oxygen, water, light, trace metals, and materials leached from the glass or plastic containers can react with the compound. The structural modifications that can improve chemical stability depend on the conditions and functional groups, including elimination, replacement or modification of unstable groups. Liphagal (33), a meroterpenoid natural product collected from the sponge Aka coralliphaga, was discovered in a screening program designed to find new isoform-selective PI3K inhibitors. 33 inhibited PI3Kα with an IC50 of 100 nM and showed an approximately 10-fold selectivity for PI3Kα compared with PI3Kγ in a fluorescent polarization enzyme bioassay [59]. It had been observed that the 6, 7 A/B ring of 33 can be rearranged to give spiro 6, 6 ring analogue 34 under acidic conditions, which led to the decrease of activity and selectivity. When ring B contracted to a six-membered ring resulted in the more stable analogue 35 with an IC50 of 66 nM and 27-fold selectivity for P13 Kα/ Kγ. At the same time, in the structure of 35, the C-8 methyl was eliminated to avoid the problem of lowered yields associated with generating mixtures of epimers at that position [60].

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Halichondrin B (26), a large polyether macrolide discovered from several sponge sources, exhibits growth inhibition on a panel of various cancer cell lines at nanomolar concentrations [46]. It suppressed the microtubule growth phase without affecting the shortening phase, and caused tubulin sequestration into non-productive aggregates [47]. This unprecedented mechanism of action also resulted in excellent activities on cancer cells resistant to other antimicrotubule agents like taxanes [48]. However, compound supply was the major hurdle for clinical development due to its complex structure since the beginning. In order to produce simpler analogues and to identify the minimum pharmacophore of 26, the testing of intermediates from the total synthesis revealed that growth inhibitory activity on DLD-1 cells could be traced back to the right half macrolactone fragment 27 [49]. Unfortunately, 27 was devoid of activity in human tumor xenogra models in contrast to 26. Subsequent studies displayed that simple furan or pyran fragments could replace the western fused pyran moiety [50]. Further functional group exploration and the replacement of the ester linkage in the macrolactone ring by a ketone led to the identification of eribulin (28), an analogue that showed the desired potency on a panel of cancer cell lines without reversing mitotic block [51]. On account of its remarkable biological profile, the drug was approved for metastatic breast cancer in 2010 in the US and 2011 in Europe [52].

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ISP-1 (29) was identified as the immunosuppressive agent from culture broths of the fungus Isaria sinclairii. It has been reported that 29 was 5- to 10-fold more efficacious than cyclosporin A in vitro and in vivo [53,54]. Structure-activity relationships (SARs) of 29 and the closely related mycestericins revealed that structural simplifications, such as reducing the double bond and removing the keto and 4-hydroxy functional groups, had no effect on activity. The removal of stereogenic centers resulted in 30 with a hydroxymethyl group instead of the carboxylic acid function of 29 [55]. Interestingly, this analogue was demonstrated to be more active and less toxic in vivo. Subsequent improvement of the activity and safety profile was acquired by lessening the linear alkyl chain length from C18 to C14, leading to the simplified analogue 31 [56]. The number of rotatable bonds was decreased through the introduction of a 1, 4-phenyl moiety into the linear alkyl chain. A systematic shift of the phenyl ring along the alkyl chain finally resulted in optimum compound 32 with further efficacy improvement, which turned out to be 100 times more potent than cyclosporin A [57]. As a result, 32 was the first oral

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Curcumin (36), a yellow principal polyphenol curcuminoid, was extracted from the popular Indian spice turmeric (Curcuma longa) [61]. 36 shows a variety of biological and cellular activities including antioxidant, anti-inflammatory, anticancer and hypocholesterolemic properties [62]. However, poor bioavailability and pharmacokinetic profiles due to its instability under alkaline and light conditions have limited its clinical application. 36 can exist in solution under physiological pH conditions as a tautomeric mixture of keto and enol forms, and the enol form (37) was found to be responsible for the instability of 36 [63–65]. It was reported previously that the presence of the β-diketone moiety may be essential for the biological activity of 36 [66,67]. However, recent studies reported that curcumin derivatives without the β-diketone retained their anti-proliferative activities. By deleting the β-diketone moiety, mono-carbonyl analogues (38) of curcumin exhibited enhanced stability in vitro and greatly improved pharmacokinetic profiles in vivo [68]. In


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addition, the β-diketone moiety via conjugation with thioureas formed divinylpyrimidinethiones (39) [69] or was replaced by isoxazole (40) or pyrazole (41) [70] with increased chemical stability.

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in many trials from Phase I to Phase III against a variety of 391 carcinomata such as solid tumor [83] and prostate cancer [84]. 392

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2.1.2. Improvement of plasma stability Compounds with certain functional groups can decompose in the bloodstream. Unstable compounds often have high clearance and short half-life, leading to poor in vivo pharmacokinetics and disappointing pharmacological performance. The plasma stability could be increased by substituting an amide for an ester or eliminating the hydrolyzable group. Epothilone B (50) is a 16-membered macrolide antibiotic produced by the myxobacterium Sorangium cellulosum [79]. Preclinical experiments have shown that 50 has potent antineoplastic activities against a wide range of tumor cell lines in vitro. Like the taxanes, 50 promoted tumor cell death by stabilizing microtubules and inducing apoptosis [80]. However, this promising in vitro activity did not translate into robust in vivo preclinical antitumor efficacy due to its poor plasma stability and unfavorable pharmacokinetic properties. Ixabepilone (51) is an analogue designed for good plasma stability, high in vivo efficacy and increased water solubility. The lactone is replaced with a lactam which is not susceptible to hydrolysis by esterases, conferring plasma stability on 51 with increased half-life from 19 to 52 h [81]. The drug was approved for monotherapy against metastatic breast cancer by the FDA in 2007 [82], and is currently

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Camptothecin (CPT, 11) was terminated in clinical trials because of its poor aqueous solubility, low metabolic stability of lactone and high in vivo hepatoxicity. Although subsequent structural modification of natural CPT has generated three antitumor agents (i.e., topotecan, irinotecan and belotecan) and a number of drug candidates with improved aqueous solubility and decreased hepatoxicity, their highly electrophilic α-hydroxylactone of the E ring can be rapidly hydrolyzed to the biologically inactive carboxylate form under the physiological conditions [88]. Furthermore, the hydrolyzed CPT carboxylate binds tightly to serum albumin, which limits the fraction of drug in the active lactone form [89]. Analogues with improved intrinsic stability were explored later. This effort has led to the development of several promising analogues including seven-membered β-hydroxy CPT (54) [90], five-membered α-hydroxy keto CPT (55) [91] and α-fluoro ether CPT (56) [92]. In the structure of 56, α-fluoro ether was designed as a metabolically stable bioisostere of lactone.

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Combretastatin A-4 (CA-4, 42), a naturally microtubulardestabilizing agent isolated from the South African tree Combretum caffrum, exhibits potent antitumour and antivascular properties both in vitro and in vivo [71]. The cis-double bond in 42 is liable and prone to isomerize to the more thermally stable trans-isomer, resulting in complete loss of the cytotoxicity. To circumvent this problem, a series of cis-restricted CA-4 analogues were developed. Replacement of the ethylene bridge with various heterocycles such as imidazole 43 [72], furan 44 [73], triazole 45 [74] and β-lactam 46 [75] provided a rigid scaffold, thus preventing cis-trans isomerisation. Further SARs study has shown that the cis-stilbene configuration of CA-4 is not essential for its biological activity. The two phenyl rings can be separated by non-cyclic linkers such as methylene 47 [76], carbonyl 48 [77] and sulfide 49 [78], which retain potent antitumour activity.

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Bottromycin A2 (52), an antibacterial peptide isolated from the fermentation broth of Streptomyces bottropensis [85], possesses potent antibacterial activities, including drugresistant strains such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) strains [86]. However, it does not show good in vivo efficacy resulting from hydrolysis of the terminal methyl ester moiety. Replacement of the ester moiety with the amide, urea or ketone led to analogues with significantly improved stability in mouse plasma, and the ketone analogue 53 exhibited potent activity against S. aureus, MRSA and VRE, comparable to that of vancomycin [87].

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2.1.3. Improvement of metabolic stability Natural drugs often encounter formidable challenges to their stability in vivo, which imposes significant limitations on the structures of NPs. Structures that are highly active in vitro


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O 2.1.4. Improvement of crossing the blood–brain barrier (BBB) BBB plays a vital role in every disease process involving the CNS and is a fatal issue in the development of all CNS drugs. In order to penetrate into the brain tissue, they must pass through the BBB. Many of the compounds that might otherwise be effective in treating CNS diseases are excluded from reaching a sufficient concentration in the brain tissue and producing the desired therapeutic effect. The brain penetration could be enhanced by lowering P-glycoprotein efflux, increasing molecular lipophilicity or reducing molecular weight. Paclitaxel (66), a structurally complex microtubulestabilizing agent discovered from the bark of the Pacific Yew, has become one of the most active cancer chemotherapeutic drugs known [108]. Although its clinical success is remarkable, 66 is not an effective agent for primary or metastatic brain cancer due to its inability to cross the BBB [109]. A primary mechanism limiting the distribution of 66 into the brain is active efflux by P-glycoprotein (Pgp) [110]. Accordingly, permeation of 66 could be substantially improved by inhibiting Pgp-mediated efflux. The introduction of the succinate at the C10 position (67) reduced apparent Pgp interactions, which imparted a 10-fold increase in brain penetration (8.47 × 10−7 cm/s) compared with 66 (0.845 × 10−7 cm/s) [111].

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Phlorizin (61), a dihydrochalcone glycoside first isolated in 1835 from the root bark of the apple tree [101], plays a key role in the history of diabetes mellitus. Its principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose co-transporter 2 located in the proximal renal tubule and mucosa of the small intestine [102]. Further development of 61 is limited by its low metabolic stability and toxic effects. The efforts to overcome the shortcomings led to first-generation analogues such as T-1095 (62) [103] and sergliflozin etabonate (63) [104]. The removal, substitution or modification of

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phenolic hydroxyl groups prevented phlorizin analogues from phase II metabolism. In addition, the glucose moiety was designed as the carbonate prodrug to further increase metabolic stability. However, no first-generation compound has been launched, due to the intrinsic metabolic lability of the O-glycoside bond, especially in humans, resulting in insufficient plasma half-life [105]. Substitution of the O-glycoside with the C-glycoside avoided hydrolysis by β-glucosidases, resulting in second-generation analogues including dapagliflozin (64) [106] and canagliflozin (65) [107] which were approved in Europe in 2012 and the US in 2013, respectively.

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may not make good drugs because they are susceptible to metabolism in vivo. There are two types of reactions including PhaseIandIImetabolisms. The major reaction of phaseImetabolism includes oxidation and reduction, while the major reactions of phaseIImetabolism contain glucuronidation and sulfation. Both of these types of reactions produce more polar products with higher aqueous solubility, so they are more readily excreted from the body via bile and urine. Metabolism increases clearance, reduces exposure, and is a major cause of low bioavailability. Structural modifications that reduce compound binding or reactivity at the labile site will increase metabolic stability. Strategies commonly include blocking metabolic site by adding other blocking groups, removing labile functional groups and replacing unstable groups. Lipoxin A4 (LXA4, 57) is a structurally and functionally distinct natural eicosanoid with potent immunomodulatory and anti-inflammatory activities [93,94]. 57 has been shown to suppress inflammation upon binding to its receptor (ALXR or hFPRL1), a G-protein-coupled receptor known to play a key role in modulating inflammation [95]. Therapeutic application of 57, however, is greatly hampered due to its chemical instability and rapid metabolism in vivo. First-generation analogues were designed to minimize rapid inactivation of 57 via ω-oxidation or oxidation at the 15(S)-alcohol by prostaglandin dehydrogenase (PGDH) [96]. Among which, 58 was obtained by substituting a fluorinated phenoxy group for the alkyl tail and by inverting the stereochemistry at C-15 to the Risomer (15-epi) based on the fact that 15-epi-LXA4 was equipotent in vitro assays to 57 but was a poorer substrate for PGDH [97]. Although 57 was efficacious in various models, it was cleared from the mouse within 15 min after intravenous injection by β-oxidation [98]. To overcome this catabolic pathway, a second generation 3-oxa-LXA4 analogue 59 was designed and synthesized, which possessed a single stable pharmacophore but still had a short half-life in vivo due to its light- or acid-sensitive trihydroxytetraene structure [99]. Replacement of the tetraene moiety with the trienyne unit led to a more stable analogue 60, which is a topically and orally active anti-inflammatory agent currently under development [99,100].

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Compound 68, a novel triterpene monoglycoside isolated from the extracts of the black cohosh plant (Actaea racemosa), acts as a γ-secretase modulator showing a comparatively selective pharmacology (Aβ42 IC50 = 0.1 μM, Aβ40 IC50 = 2.7 μM) via screening of natural product extracts for


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lines containing K562, MCF-7, Bel-7402, and MGC-803 (IC50 = 1.12, 0.68, 0.50 1.09 μM, respectively) than that of 7 (IC50 = 4.76, 14.60, 7.48 and 5.69 μM, respectively) and benzoic acid mustard (IC50 N 140 μM), and also exhibited an approximately 8-fold higher selective cytotoxicity toward the cancer cells, which was higher than those of 7 (2.5-fold) and clinically used chlorambucil (2-fold) [119].

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Oleanolic acid (78), a triterpenoid compound extracted from many Asian herbs, such as Fructus ligustri lucidi, Fructus forsythiae, Radix ginseng, and Akebia trifoliate, exhibits hepatoprotective, anti-inflammatory, antitumor, antioxidant and antiglycative activities [120]. 78 has been shown to inhibit tumor initiation and promotion, and to induce tumor cell differentiation and apoptosis. Despite its positive mode of action, the antitumor activity of 78 is relatively weak. By introducing a nitrate NO donor and L-valine at the 3-positon and 28-positon of 78, compound 79 showed effective activities against four human cancer cell lines (HepG2, MCF-7, A549, HCT-116), especially in A549 cells with an IC50 value 2-fold lower (IC50 = 7.5 μM) than that of the positive control cisplatin (IC50 = 16.5 μM) [121]. The introduction of a nitrate NO donor improves the antitumor activity because of the synergistic action of the cytotoxic NO donor and 78. Furthermore, the L-valine moiety can be selectively transported by peptide transporter 1 to the tumor cells, resulting in increase of selectivity. In addition, another promising prodrug 80 obtained through the introduction of a glutathione s-transferase π-activated O2 -diazeniumdiolate NO donor and liver-specific galactose at the 3-positon and 28-positon of 78, significantly improved the potency and selectivity of 78 [122].

583 584 585 586

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2.1.5. Improvement of potency and selectivity The therapeutic effectiveness of most natural drugs today is encumbered by the low potency or undesired side-effects associated with their poor selectivity toward targeted cells. Intensive efforts have been made to endow natural agents with enhanced efficacy and selectivity. (±)-XJP (71), (±)-7, 8-dihydroxy-3-methyl-isochroman4-one, a novel natural polyphenolic compound isolated from the banana (Musa sapientum L.) peel, displayed potent antihypertensive activity in both acute and therapeutic antihypertensive tests in renal hypertensive rats [115,116]. (±)-XJP-B (72), an analogue of 71, was more active than 71 in spontaneously hypertensive rats (SHRs). However, the antihypertensive effects of both 71 and 72 are still not potent enough for therapeutic use. By coupling nitric oxide (NO)-donor moieties with 71 and 72, compounds 73, 74 and 75 reduced blood pressure by nearly 40% in SHRs, which was obviously superior to that of the lead compounds and comparable to that of reference drug captopril [117]. Moreover, by connecting N-substituted isopropanolamine functionalities, the classic side chains of β-blockers, to a phenolic oxygen of 71 or 72, compound 76 was achieved and exhibited potent β1-adrenoceptor blocking effect comparable to the well-known antihypertensive drug propranolol [118].

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their ability to reduce Aβ42 relative to Aβ40 in a cell-based assay [112]. However, the high molecular weight (MW) and tPSA (155 Å2, a property that has been strongly correlated with poor CNS permeability) of 68 limits its clinical development for CNS drugs. Replacement of the C3 glycoside with a MW-decreasing and more lipophilic morpholine led to an analogue 69 with significantly improved CNS exposure (B/P = 1.7, Aβ42 IC50 = 0.07 μM, Aβ40 IC50 = 2.3 μM, F = 37%) [113]. Furthermore, conversion of the C24 acetate to an ether and substitution of the C3 morpholine nitrogen with N-methyl cyclobutanamine provide an analogue 70 with a better pharmacokinetic profile (B/P = 0.55, Aβ42 IC50 = 0.1 μM, Aβ40 IC50 = 2.1 μM, F = 75%) [114].

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Although oridonin (7) showed a unique and safe antitumor activity, the development of 7 for cancer therapy is hampered, to a large extent, by its relatively moderate potency. Compound 77 achieved by conjugation of 7 with benzoic acid mustard, showed more potent activities against four human cancer cell

2.1.6. Employment of prodrug strategy The prodrug design is a versatile, powerful method that can be applied to NPs with the aim of increasing aqueous solubility, improving lipophilicity, strengthening metabolic stability, enhancing transporter-mediated absorption, such as 79, and achieving site-specific delivery, such as 80. Rapamycin (81), a macrolide initially isolated from Streptomyces hygroscopicushas [123], is a highly specific mTOR inhibitor displaying antifungal, immunosuppressive, anticancer, neuroprotective and antiaging activities [124]. However, the poor aqueous solubility and metabolic instability impeded clinical development of 81 in cancer therapy [125]. Multiple analogues of 81 have been designed for improving its solubility and stability.


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Temsirolimus (82), designed as a water-soluble ester prodrug with increased stability, demonstrated rapamycin-comparable antineoplastic potency against a panel of National Cancer Institute (NCI) human tumor cell lines, with an IC50 value frequently b10 nM [126]. In 2007, the drug was approved by the FDA for intravenous administration in oncology [127].

derivatives [136], and others being applied for (±)-XJP 675 derivatives [137], β-elemene derivatives [138], etc. 676 3. Conclusion

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NPs as secondary metabolites have played a key role in drug discovery and constitute a prolific source of novel lead compounds or pharmacophores for medicinal chemistry. As compared to synthetic molecules, NPs possess structural diversity and complexity, more stereogenic centers and fewer halogen or nitrogen atoms. They form a rather heterogeneous class of compounds differentiated by their source organisms, biosphere of origin, and biological role. Due to the high potential to show excellent biological activities, NPs have been the major source of therapeutic agents. Druggability optimization of NPs is intent to increase solubility, potency, stability and selectivity, etc. Under the premise of maintaining or enhancing the activity, selective modifications of NPs overcome corresponding deficiencies and shortcomings according to the principles and rules of pharmacology and medicinal chemistry, advancing NPs from leads to available drugs.

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Acknowledgments

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This study was financially supported by a grant from the National Natural Science Funds (No. 81373280; 81302635; 81273377) and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404).

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2.1.7. The intellectual property attainment status of NPs NPs are now harder to get patented, which greatly affects NP intellectual property strategy. The US Patent and Trademark Office (USPTO) on March 4, 2014 issued new guidelines that natural law, material or phenomenon could not obtain patent protection [133]. Known NPs discovered with new activity or even NPs isolated first won't boost the chances of patent eligibility. While natural analogues that be modified with substituents, side chains, point mutations and so on, overstep the rule [134]. Thus it is essential for proper modification of natural structures so as to attain intellectual properties. Recently, we have carried out a large body of investigations on the structural modification of NPs and some achievements have also been made including three granted patents for oridonin derivatives [135], four for 23-hydroxybetulinic acid

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Berberine (83), an isoquinoline alkaloid extracted from Chinese herbs Coptis chinensis, has been extensively used as traditional medicines for the treatment of gastroenteritis and secretory diarrhea [128], and has also been found to have a variety of pharmacological and biological activities, such as antifungal, antineoplastic, anti-inflammatory, anti-hyperglycemic and anti-hyperlipidemic effects [129]. However, for its hydrophilic in nature, 83 is absorbed poorly in the intestines, thus leading to low oral bioavailability [130]. Berberrubine (84), which is an active metabolite of 83 after first pass metabolism, showed a slightly lower lipidlowing activity than that of 83 [131,132]. The ester or ether prodrugs were designed and prepared with improved lipophilicity and oral bioavailability through modification of phenolic hydroxyl of 84. Among them, compound 85 bearing a palmitate exhibited a moderate Log P value and hydrolysis rate in blood, and reduced blood CHO and LDL-c by 35.8% and 45.5%, respectively, similar to that by 83 [132].

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Insights into drug discovery from natural medicines using reverse pharmacokinetics.

Natural Products: Insights into Leishmaniasis Inflammatory Response.

Insights from systems pharmacology into cardiovascular drug discovery and therapy.

Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes.

A New Golden Age of Natural Products Drug Discovery.

The use of natural products in colorectal cancer drug discovery.

Pharmacognosy: Science of natural products in drug discovery.

A historical overview of natural products in drug discovery.

New natural products as new leads for antibacterial drug discovery.

Insights into natural products biosynthesis from analysis of 490 polyketide synthases from Fusarium.

System-level multi-target drug discovery from natural products with applications to cardiovascular diseases.

Culture-independent discovery of natural products from soil metagenomes.

Genome-guided discovery of diverse natural products from Burkholderia sp.

Preparative chromatography and natural products discovery.

Structural insights into ribosome translocation.

The re-emergence of natural products for drug discovery in the genomics era.

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

Natural products and drug discovery: a survey of stakeholders in industry and academia.

An introduction to the special issue on pharmaceuticals, drug discovery and natural products.

Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs.

Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes.

Something old, something new: revisiting natural products in antibiotic drug discovery.

New Insights into the Biosynthetic Logic of Ribosomally Synthesized and Post-translationally Modified Peptide Natural Products.

Structural insights into +1 frameshifting promoted by expanded or modification-deficient anticodon stem loops.