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1.  HIV Entry Inhibitors and Their Potential in HIV Therapy 
Medicinal research reviews  2009;29(2):369-393.
This review discusses recent progress in the development of anti-HIV agents targeting the viral entry process. The three main classes (attachment inhibitors, co-receptor binding inhibitors, and fusion inhibitors) are further broken down by specific mechanism of action and structure. Many of these inhibitors are in advanced clinical trials, including the HIV maturation inhibitor bevirimat, from the authors’ laboratories. In addition, the CCR5 inhibitor maraviroc has recently been FDA-approved. Possible roles for these agents in anti-HIV therapy, including treatment of virus resistant to current drugs, are also discussed.
PMCID: PMC3773846  PMID: 18720513
HIV entry inhibitors; attachment inhibitors; co-receptor binding inhibitors; fusion inhibitors; maraviroc (MVC; UK-427, 857); enfuvirtide (T20;fuzeon); bevirimat (DSB;PA-457)
2.  Dual-functional abeo-Taxane Derivatives Destabilizing Microtubule Equilibrium and Inhibiting NF-κB Activation 
Journal of medicinal chemistry  2013;56(11):4749-4757.
Taxchinin A, with a 11(15→1)-abeo-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis. In our design of dual-functional antitumor abeo-taxane derivatives, two fragments from antitumor agents with different molecular targets (the N-acyl-3′-phenylisoserine side chain from the antimitotic agent paclitaxel and an α,β-unsaturated carbonyl system from NF-κB inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity towards colon cancer, melanoma and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. Based on the NCI-60 assay data, structure-activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-κB activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural taxoid scaffolds.
PMCID: PMC3755589  PMID: 23725535
3.  Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-type Diterpenes and Biflavonoid from Stellera chamaejasme 
Journal of natural products  2013;76(5):852-857.
Five novel tigliane-type diterpenes, stelleracins A–E (3–7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3–5 showed potent anti-HIV activity (EC90 0.00056–0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4–17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates.
PMCID: PMC3715147  PMID: 23611151
4.  Songaricalarins A–E, Cytotoxic Oplopane Sesquiterpenes from Ligularia songarica# 
Journal of natural products  2012;76(3):305-310.
Five new highly oxygenated oplopane sesquiterpenes, songaricalarins A–E (1–5), and two known analogues (6 and 7) were isolated from the roots and rhizomes of Ligularia songarica. Their structures and configurations were elucidated by spectroscopic methods, including 2D-NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction. All compounds were evaluated for in vitro cytotoxic activity against cultured A-549, MCF-7, KB, and KBVIN cells, and 4 exhibited cytotoxicity with EC50 values of 4.9, 0.8, 3.4, and 3.2 µg/mL, respectively.
PMCID: PMC3553309  PMID: 23043462
5.  New Betulinic Acid Derivatives for Bevirimat-Resistant Human Immunodeficiency Virus Type-1 
Journal of medicinal chemistry  2013;56(5):2029-2037.
Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally-occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.
PMCID: PMC3600082  PMID: 23379607
Betulinic acid; Bevirimat; HIV-1; Maturation inhibitors; Bevirimat-resistance
6.  Synthesis and Biological Evaluation of N-Alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a New Class of Tubulin Polymerization Inhibitors 
Bioorganic & medicinal chemistry  2012;21(3):632-642.
Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KBVIN, and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI50 values of 0.19 to 0.41 μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC50 1.4–1.7 μM) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity.
PMCID: PMC3546147  PMID: 23274123
N-alkyl-N-phenylpyridin-2-amines; cytotoxicity; tubulin polymerization inhibitors; colchicine binding site
7.  Anticancer Principles from Medicinal Piper (胡椒 Hú Jiāo) Plants 
The ethnomedical uses of Piper (胡椒 Hú Jiāo) plants as anticancer agents, in vitro cytotoxic activity of both extracts and compounds from Piper plants, and in vivo antitumor activity and mechanism of action of selected compounds are reviewed in the present paper. The genus Piper (Piperaceae) contains approximately 2000 species, of which 10 species have been used in traditional medicines to treat cancer or cancer-like symptoms. Studies have shown that 35 extracts from 24 Piper species and 32 compounds from Piper plants possess cytotoxic activity. Amide alkaloids account for 53% of the major active principles. Among them, piplartine (piperlongumine) shows the most promise, being toxic to dozens of cancer cell lines and having excellent in vivo activity. It is worthwhile to conduct further anticancer studies both in vitro and in vivo on Piper plants and their active principles.
PMCID: PMC4032846  PMID: 24872928
Amide alkaloids; Anticancer; Cytotoxicity; Piper; Piperaceae
8.  1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl Esters, a Novel Compound Class with Potent Chemoreversal Activity 
1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, which share a fragment from (±)-3′-O-4′-O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and 3′R,4′R-disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP), exhibited remarkable chemoreversal activity on multi-drug resistant human nasopharyngeal carcinoma (KB) when combined with three anti-cancer drugs, paclitaxel, vincristine and doxorubicin. Among 15 novel synthesized analogs, bis-trimethoxybenzoyl derivative 15 was the most active (340-fold more active than verapamil when used with vincristine) followed by two di-cinnamoyl derivatives, 10 and 11, and then di-cyclohexanecarbonyl derivative 9. All aliphatic chain derivatives, 3–5, showed no activity. Structure-activity relationship study indicated that a di-ester structure was critical to enhance the activity resulting from the maintenance of the spatial arrangement proposed by the pharmacophore based on the verapamil-binding site. Further mechanism of action study showed 15 inhibited mainly P-glycoprotein efflux pump function, while 13 exhibited an additional multidrug resistance-associated protein efflux pump function.
PMCID: PMC3508342  PMID: 23122817
1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters; Chemoreversal activity; KB cell line
9.  Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators 
ACS Medicinal Chemistry Letters  2012;3(11):925-930.
Accumulation of aberrant protein aggregates, such as amyloid β peptide (Aβ), due to decreased proteasome activities, might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC50 of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an α to β orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of Aβ on the proteasome.
PMCID: PMC3544189  PMID: 23330053
proteasome activator; lithocholic acid; Alzheimer's disease; amyloid β
10.  Anti-AIDS Agents 90. Novel C-28 Modified Bevirimat Analogs as Potent HIV Maturation Inhibitors 
Journal of medicinal chemistry  2012;55(18):8128-8136.
In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by two-fold, while compounds 40–41 and 48–49, with C-28 piperazine or piperidine amide substitutions, increased the activity by three- to fifteen-fold. The best new compound 41 exhibited an anti-HIV IC50 value of 0.0059 μM, compared with 0.087 μM for 2. All of the active compounds showed only anti-maturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the anti-maturation activity of 2, without any anti-entry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.
PMCID: PMC3478670  PMID: 22978745
11.  Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents† 
Natural product reports  2009;26(10):1321-1344.
This article reviews the antitumor and anti-HIV activities of naturally occurring triterpenoids, including the lupane, ursane, oleanane, lanostane, dammarane, and miscellaneous scaffolds. Structure–activity relationships of selected natural compounds and their synthetic derivatives are also discussed.
PMCID: PMC3773821  PMID: 19779642
12.  Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates 
Journal of medicinal chemistry  2012;55(16):7219-7229.
Twenty-one new 4-substituted diarylaniline compounds (DAANs) (Scheme 2, series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to sub-nanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the sub-nanomolar level (0.29–0.87 nM), and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Drug-like physicochemical property assessments revealed that the most active DAANs (EC50 <10 nM) have better aqueous solubility (>1–90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface area (PSA) (<140 Å2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
PMCID: PMC3462592  PMID: 22856541
13.  Synthesis of Betulinic Acid Derivatives as Entry Inhibitors against HIV-1 and Bevirimat-Resistant HIV-1 Variants 
Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
PMCID: PMC3426442  PMID: 22818973
HIV-1; Entry inhibitor; Maturation inhibitor; Betulinic acid; Berivimat; Berivimat-resistance
14.  Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators 
ACS medicinal chemistry letters  2012;3(11):925-930.
Accumulation of aberrant protein aggregates, such as amyloid beta peptide (Aβ), due to decreased proteasome activities might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC50 of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an alpha to beta orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of Aβ on the proteasome.
PMCID: PMC3544189  PMID: 23330053
proteasome activator; lithocholic acid; Alzheimer's disease; amyloid beta
15.  Antitumor Agents 295. E-ring Hydroxylated Antofine and Cryptopleurine Analogs as Antiproliferative Agents: Design, Synthesis, and Mechanistic Studies 
Journal of medicinal chemistry  2012;55(15):6751-6761.
Various E-ring hydroxylated antofine and cryptopleurine analogs were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of non-small cell lung cancer (NSCLC) cell lines, in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating Hedgehog pathway-driven tumorigenesis.
PMCID: PMC3422873  PMID: 22823514
16.  Antitumor agents 294. Novel E-ring-modified camptothecin–4β-anilino-4′-O-demethylepipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents 
Bioorganic & medicinal chemistry  2012;20(14):4489-4494.
Two conjugates (1 and 2) of camptothecin (CPT) and 4β-anilino-4′-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.
PMCID: PMC3389137  PMID: 22698783
Topoisomerase; cytotoxicity; camptothecin (CPT); etoposide (VP-16); epipodophyllotoxin; conjugates
17.  Antitumor agents 290. † Design, synthesis, and biological evaluation of new LNCaP and PC-3 cytotoxic curcumin analogs conjugated with anti-androgens 
Bioorganic & medicinal chemistry  2012;20(13):4020-4031.
In our continuing study of curcumin analogs as potential anti-prostate cancer drug candidates, 15 new curcumin analogs were designed, synthesized and evaluated for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Twelve analogs (5-12, 15, 16, 19, and 20) are conjugates of curcumin (1) or methyl curcumin (2) with a flutamide- or bicalutamide-like moiety. Two compounds (22 and 23) are C4-mono- and difluoro-substituted analogs of dimethyl curcumin (DMC, 21). Among the newly synthesized conjugates compound 15, a conjugate of 2 with a partial bicalutamide moiety, was more potent than bicalutamide alone and essentially equipotent with 1 and 2 against both prostate tumor cell lines with IC50 values of 41.8 μM (for LNCaP) and 39.1 μM (for PC-3). A cell morphology study revealed that the cytotoxicity of curcumin analogs or curcumin-antiandrogen conjugates detected from both prostate cancer cell lines might be due to the suppression of pseudopodia formation. A molecular intrinsic fluorescence experiment showed that 1 accumulated mainly in the nuclei, while conjugate 6 was distributed in the cytosol. At the tested conditions, antiandrogens suppressed pseudopodia formation in PC-3 cells, but not in LNCaP cells. The evidence suggests that distinguishable target proteins are involved, resulting in the different outcomes toward pseudopodia suppression.
PMCID: PMC3376200  PMID: 22672984
Synthesis; Curcumin analogs; Conjugates; Cytotoxicity; Anti-prostate cancer; Morphology
18.  Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents 
Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7-13 were generally less active than pyranoxanthones 14-21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8 μ g/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control.
PMCID: PMC3374489  PMID: 22595179
1,3,6-Trihydroxy-9H-xanthen-9-one; Gambogic acid (GA); Prenylxanthones; Pyranoxanthones; Cytotoxicity; Anti-inflammatory activity
19.  Antitumor Agents 293. Non-toxic Dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) Analogs Chemosensitize Multidrug Resistant Cancer Cells to Clinical Anticancer Drugs 
Journal of Medicinal Chemistry  2012;55(11):5413-5424.
Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogs were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine resistant nasopharyngeal carcinoma) cells, a multi-drug resistant cell line over-expressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2′-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 16 and 23 showed 5–10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analog 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogs against both non-MDR and MDR cells, suggesting that DDB analogs serve as the novel lead compounds for the development of chemosensitizers to overcome MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogs dramatically elevated cellular concentration of anticancer drugs.
PMCID: PMC3375343  PMID: 22612652
20.  Cytotoxic and Anti-HIV Phenanthroindolizidine Alkaloids from Cryptocarya chinensis 
Natural product communications  2012;7(6):725-727.
Bioassay-guided fractionation of the cytotoxic ethanol extract of Cryptocarya chinensis has led to the isolation of 11 compounds, including two phenanthroindolizidine alkaloids [(−)-antofine (1) and dehydroantofine (2)], five pavine alkaloids (3–7), and four proaporphine alkaloids (8–11). The structures of the isolated compounds were determined by means of NMR spectroscopic methods, and supported by HRMS and optical rotation data. Compounds 1 and 2 showed cytotoxic activity against four cancer cell lines, L1210, P388, A549, and HCT-8, with 1 being the most potent against A549 and HCT-8 with EC50 values of 0.002 and 0.001 μg/mL, respectively. In addition, 2 is first reported to exhibit significant anti-HIV activity.
PMCID: PMC3666852  PMID: 22816292
Cryptocarya chinensis; Phenanthroindolizidine alkaloid; Pavine alkaloids; Proaporphine alkaloids
21.  Anti-AIDS agents 89. Identification of DCX derivatives as anti-HIV and chemosensitizing dual function agents to overcome P-gp-mediated drug resistance for AIDS therapy 
In this study, 19 dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-dihydropyranoxanthone (DCX) derivatives, previously discovered as novel anti-HIV agents, were evaluated for their potential to reverse multi-drug resistance (MDR) in a cancer cell line over-expressing P-glycoprotein (P-gp). Seven compounds fully reversed resistance to vincristine (VCR) at 4 μM, a 20-fold enhancement compared to the first generation chemosensitizer, verapamil (4 μM). The mechanism of action of DCPs and DCXs was also resolved, since the most active compounds (3, 4, and 7) significantly increased intracellular drug accumulation due, in part, to inhibiting the P-gp mediated drug efflux from cells. We conclude that DCPs (3 and 4) and DCXs (7, 11, and 17) can exhibit polypharmacologic behavior by acting as dual inhibitors of HIV replication and chemoresistance mediated by P-gp. As such, they may be useful in combination therapy to overcome P-gp-associated drug resistance for AIDS treatment.
PMCID: PMC3331909  PMID: 22465634
pyranochromone derivatives; chemoresistance; P-glycoprotein (P-gp) inhibitors; anti-HIV agents; dual function inhibitors
22.  Anti-AIDS agents 88. Anti-HIV conjugates of betulin and betulinic acid with AZT prepared via click chemistry 
Tetrahedron letters  2012;53(15):1987-1989.
In the present study, a new strategy to link AZT with betulin/betulinic acid (BA) by click chemistry was designed and achieved. This conjugation via a triazole linkage offers a new direction for modification of anti-HIV triterpenes. Click chemistry provides an easy and productive way for linking two molecules, even when one of them is a large natural product. Among the newly synthesized conjugates, compounds 15 and 16 showed potent anti-HIV activity with EC50 values of 0.067 and 0.10 µM, respectively, which are comparable to that of AZT (EC50: 0.10 µM) in the same assay.
PMCID: PMC3375835  PMID: 22711941
Betulin; Betulinic acid; AZT; Anti-HIV; Click chemistry
23.  Optimization of 2,4-Diarylanilines as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors 
The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a–9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC50 0.53 nM) and several resistant viral strains (EC50 0.36 – 3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs.
PMCID: PMC3309038  PMID: 22406117
Diarylaniline; NNRTIs; lead optimization; anti-HIV agents
24.  Antitumor Agents 289. Design, Synthesis, and Anti-breast Cancer Activity in Vivo of 4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) Analogues with Improved Water Solubility# 
Journal of Natural Products  2012;75(3):370-377.
Previously, we reported that 4-amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogues, which were developed from the lead natural produce neo-tanshinlactone, are potent cytotoxic agents. In order to improve on their water solubility, the diamino analogues and related salts were designed. All synthesized compounds were assayed for cytotoxicity, and selected compounds were evaluated for in vivo anti-mammary epithelial proliferation activity in wild-type mice and mice predisposed for mammary tumors due to Brca1/p53 mutations. The new derivatives 10, 16 (ABO), 22, and 27 (ATBO) were the most active analogues with IC50 values of 0.038–0.085 μM in the cytotoxicity assay. Analogue 10 showed around 50-fold improved water solubility compared with the prior lead ABO compound 4-[(4'-methoxyphenyl)amino]-2H-benzo[h]chromen-2-one (3). Compounds 3, 4, 10, and 22 significantly reduced overall numbers of mammary cells as indicated by the reduction of mammary gland branching in mutant mice. A one-week treatment with 10 resulted in 80% reduction in BrdU-positive cells in the cancer prone mammary gland. These four compounds had differential effects on cellular proliferation and apoptosis in wild-type mouse and mouse model of human breast cancers. Compound 10 merits further development as a promising anticancer clinical trial candidate.
PMCID: PMC3311758  PMID: 22304236
25.  Ortho-Quinone tanshinones directly inhibit telomerase through an oxidative mechanism mediated by hydrogen peroxide 
The tanshinone natural products possess a variety of pharmacological properties including anti-bacterial, anti-inflammatory, anti-oxidant, and anti-neoplastic activity. The molecular basis of these effects, however, remains largely unknown. In the present study, we explored the direct effect of tanshinones on the enzyme telomerase. Telomerase is up-regulated in the majority of cancer cells and is essential for their survival, making it a potential anti-cancer drug target. We found that the ortho-quinone tanshinone II-A inhibits telomerase in a time- and DTT-dependent fashion, and the hydrogen peroxide scavenger catalase protected telomerase from inactivation. These findings demonstrate that ortho-quinone containing tanshinones can inhibit telomerase owing to their ability to generate reactive oxygen species. The results also provide evidence that telomerase is directly and negatively regulated by reactive oxygen species.
PMCID: PMC3559103  PMID: 22044621
telomerase; ortho-quinones; hydrogen peroxide; reactive oxygen species; tanshinones

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