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1.  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.
doi:10.1021/np300532p
PMCID: PMC3553309  PMID: 23043462
2.  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.
doi:10.1016/j.bmc.2012.11.047
PMCID: PMC3546147  PMID: 23274123
N-alkyl-N-phenylpyridin-2-amines; cytotoxicity; tubulin polymerization inhibitors; colchicine binding site
3.  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.
doi:10.1021/jm3001218
PMCID: PMC3422873  PMID: 22823514
4.  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.
doi:10.1016/j.bmcl.2012.04.084
PMCID: PMC3374489  PMID: 22595179
1,3,6-Trihydroxy-9H-xanthen-9-one; Gambogic acid (GA); Prenylxanthones; Pyranoxanthones; Cytotoxicity; Anti-inflammatory activity
5.  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.
doi:10.1021/jm300378k
PMCID: PMC3375343  PMID: 22612652
6.  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.
doi:10.1016/j.bmcl.2012.03.037
PMCID: PMC3331909  PMID: 22465634
pyranochromone derivatives; chemoresistance; P-glycoprotein (P-gp) inhibitors; anti-HIV agents; dual function inhibitors
7.  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.
doi:10.1021/np2007878
PMCID: PMC3311758  PMID: 22304236
8.  Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents 
Medicinal chemistry  2011;1(101):1000101.
Drug usefulnessis frequently obstructed by the incidence of the multidrug resistance (MDR) phenotype and severe adverse effects. Exploiting collateral sensitive(CS)agents (in this case also called MDR-selective agents), which selectively target only MDR cells, is an emerging and novel approach to overcome MDR in cancer treatment. In prior studies, we found that 4′-methyl-6,6,8-triethyldesmosdumotin B (4′-Me-TEDB, 2) is an MDR-selective synthetic flavonoid with significant in vitro anticancer activity against a MDR cell line (KB-Vin) but without activity against the parent cells (KB) as well as other non-MDR tumor cells. Our recent results suggest the absolute MDR-selectivity varies depending on the cell-line system. In order to explore this further and to better understand the critical pharmacophores, we have synthesized nine novel analogues of 2, which contain heteroaromatic as well ascycloalkyl B-rings. The new compounds were evaluated for cytotoxicity to explore the effect of B-ring modifications on MDR-selectivity. All analogues, except 7, 9 and 10, were identified as significant MDR-selective compounds. This observation solidifies the importance of the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione skeleton (AC-ring system) for the pharmacological activity and establishes the B-ring as less critical for the broader spectrum MDR-selectivity. Notably, 3-furanyl (3)and 2-thiophenyl (6)analogues displayed substantial MDR–selectivity with KB/KB-Vin ratios of >12 and 16, respectively. Furthermore, 3 and 6 also exhibited MDR–selectivity in a second set of paired cell lines, the MDR/non-MDR hepatoma-cell system. Interestingly, a cyclohexyl analogue (11) showed moderate inhibition of A549, DU145, and PC-3 cell growth, while the other compounds were inactive. These new findings are discussed in terms of current understanding of mechanism and structure–activity relationship (SAR) of our novel MDR-selective flavonoids.
doi:10.4172/2161-0444.1000101
PMCID: PMC3537172  PMID: 23293751
Triethyldesmosdumotin B; Multi-drug resistance; MDR-selectivity (collateral sensitivity); Heteroaromatic ring; Cycloalkyl ring
9.  Cytotoxic esterified diterpenoid alkaloid derivatives with increased selectivity against a drug-resistant cancer cell line 
C-6 Esterifications of delpheline (1) were carried out to provide 20 new diterpenoid alkaloid derivatives (4–22, 24). Three natural alkaloids (1–3) and all synthesized compounds (4–25) were evaluated for cytotoxic activity against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines and interestingly, showed an improved drug resistance profile compared to paclitaxel. Particularly, 6-(4-fluoro-3-methylbenzoyl)delpheline (22) displayed 2.6-fold greater potency against KB-VIN cells compared with the parental non-drug resistant KB cells. 6-Acylation of 1 appears to be critical for producing cytotoxic activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents.
doi:10.1016/j.bmcl.2011.11.026
PMCID: PMC3248953  PMID: 22142543
Delpheline; C19-diterpenoid alkaloid; Cytotoxicity
10.  Cytotoxic geranylflavonoids from Bonannia graeca 
Phytochemistry  2011;10.1016/j.phytochem.2011.03.005.
The analysis of the aerial parts of Bonannia graeca led to the isolation and characterization of two new polar geranylated flavonoids (6 and 7). The structure elucidation was performed by extensive spectroscopic methods (1D and 2D NMR) and comparison with literature data. All natural flavonoids isolated from B. graeca (1–7) and some synthetic derivatives (8–11) were tested for cytotoxic activity against four human tumor cell lines. Preliminary structure-activity relationship correlations are discussed.
doi:10.1016/j.phytochem.2011.03.005
PMCID: PMC3151324  PMID: 21459391
Bonannia graeca; Apiaceae; Geranylflavonoids; Cytotoxic Activity
11.  Bioactive Constituents from the Roots of Panax japonicus var. MAJOR and Development of a LC-MS/MS Method for Distinguishing between Natural and Artifactual Compounds 
Journal of natural products  2011;74(4):796-802.
Two new saponins, panajaponol (1) and pseudoginsenoside RT1 butyl ester (2), together with 35 known compounds (3–37), were isolated from the roots of Panax japonicus. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis and chemical methods. Furthermore, a LC-MS/MS method was developed for confirming 2, 3, and 8 as natural compounds containing a butyl ester group. This method should be useful for distinguishing between minor natural and artifactual compounds in Panax species. Moreover, compounds 3, 6, 8, 9, 11, 13, and 15 exhibited strong inhibition of superoxide anion generation and elastase release by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB), with IC50 values ranging from 0.78 to 43.6 μM. In addition, 1 showed greater than two- to three-fold selective cytotoxic activity against KB and DU145 cancer cell lines.
doi:10.1021/np100851s
PMCID: PMC3092375  PMID: 21417387
12.  Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity 
4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research. Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the pyranone ring, we have established preliminary structure-activity relationships (SAR). Analogs 19, 20, 23, and 26–30 displayed significant tumor cell growth inhibitory activity in vitro. The most active compound 27 exhibited ED50 values of 0.059–0.090 μM.
doi:10.1016/j.bmcl.2011.02.084
PMCID: PMC3072684  PMID: 21420855
4-Amino-2H-pyran-2-one (APO) analogs; Neo-tanshinlactone; Cytotoxicity
13.  New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis 
Bioorganic & medicinal chemistry  2011;19(6):1895-1906.
A series of novel bichalcone analogs were synthesized and evaluated in lipopolysaccharide (LPS)-activated microglial cells as inhibitors of nitric oxide (NO) and for in vitro anticancer activity using a limited panel of four human cancer cell lines. All analogs inhibited NO production. Compounds 4 and 11 exhibited optimal activity with IC50 values of 0.3 and 0.5 µM, respectively, and were at least 38-fold better than the positive control. A mechanism of action study showed that both compounds significantly blocked the nuclear translocation of NF-κB p65 and up-regulation of iNOS at 1.0 µM. Compound 4 and three other analogs (3, 20, and 23) exerted significant in vitro anticancer activity GI50 values ranging from 0.70~13.10 µM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling.
doi:10.1016/j.bmc.2011.02.004
PMCID: PMC3066007  PMID: 21377368
bichalcone analogs; nitric oxide production inhibition; cytotoxicity; apoptosis
14.  Antitumor Agents 284. New Desmosdumotin B Analogues with Bicyclic B-ring as Cytotoxic and Antitubulin Agents 
Journal of medicinal chemistry  2011;54(5):1244-1255.
We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI50 values of 0.8–2.1 μM. In contrast, 1-analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistance cell line. We have now prepared and evaluated 1-analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI50 values of 0.06–0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC 50 value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.
doi:10.1021/jm1011947
PMCID: PMC3048907  PMID: 21284385
15.  Antitumor Agents 283. Further Elaboration of Desmosdumotin C Analogs as Potent Antitumor Agents: Activation of Spindle Assembly Checkpoint as Possible Mode of Action 
Bioorganic & medicinal chemistry  2011;19(5):1816-1822.
In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21–32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4′-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED50 values of 1.1–2.8 μM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED50 1.7 μM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase.
doi:10.1016/j.bmc.2011.01.001
PMCID: PMC3064560  PMID: 21296579
Desmosdumotin C; Antiproliferative activity; Human tumor cell lines; Microarray
16.  Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents 
In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6–12 and 14–24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED50 1.1–4.3 µg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED50 0.73 µg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED50 1.7 and 0.85 µg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1f11/f11p53f5&6/f5&6Crec mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands.
doi:10.1016/j.bmcl.2010.11.077
PMCID: PMC3011818  PMID: 21147529
2-(furan-2-yl)naphthalen-1-ol analogs; structure-activity relationships; anti-breast tumor agents
17.  Antitumor Agents 281. Design, Synthesis, and Biological Activity of Substituted 4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one Analogs (ATBO) as Potent In Vitro Anticancer Agents 
In our exploration of new biologically active chemical entities, we designed and synthesized a novel class of antitumor agents, substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs. We evaluated their cytotoxic activity against seven human tumor cell lines from different tissues, and established preliminary structure-activity relationships (SAR). All analogues, except 8, 9, and 25-27, displayed potent tumor cell growth inhibitory activity. Especially, compounds 15 and 33 with a 4-methoxyphenyl group at position C-4 were extremely potent with ED50 values of 0.008-0.064 μM and 0.035-0.32 μM, respectively. Compound 15 was the most potent analog compared with structurally related neo-tanshinlactone (e.g., 1) and 4-amino-2H-benzo[h]chromen-2-one (ABO, e.g., 4) analogs, and thus merits further exploration as an anti-cancer drug candidate.
doi:10.1016/j.bmcl.2010.10.074
PMCID: PMC3053047  PMID: 21087859
4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-ones (ATBO); Cytotoxic activity; Neo-tanshinlactone
18.  Antitumor Agents 286. Design, Synthesis and Structure-Activity Relationships of 3′R,4′R-Disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP) Analogs as Potent Chemosensitizers to Overcome Multidrug Resistance 
Journal of medicinal chemistry  2010;53(24):8700-8708.
In this study, various 3′R,4′R-disubstituted-2′,2′-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogs (5–28) were synthesized and evaluated against a multi-drug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogs exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI50 value of VCR by 12–349-fold. At a concentration of 1μg/mL, three compounds, 11, 14 and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a twofold increase compared to verapamil, a first generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3′ and 4′ substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogs results from inhibition of P-glycoprotein (P-gp) over-expressed in MDR cancer cells.1
doi:10.1021/jm101249z
PMCID: PMC3074582  PMID: 21082774
19.  Camphoratins A–J, Potent Cytotoxic and Anti-inflammatory Triterpenoids from the Fruiting Body of Taiwanofungus camphoratus 
Journal of natural products  2010;73(11):1756-1762.
Ten new triterpenoids, camphoratins A–J (1–10), along with 12 known compounds were isolated from the fruiting body of Taiwanofungus camphoratus. Their structures were established by spectroscopic analysis and chemical methods. Compound 10 is the first example of a naturally occurring ergosteroid with an unusual cis-C/D ring junction. Compounds 2–6 and 11 showed moderate to potent cytotoxicity with EC50 values ranging from 0.3 to 3 μM against KB and KB-VIN human cancer cell lines. Compounds 6, 10, 11, 14–16, 18, and 21 exhibited anti-inflammatory NO-production inhibition activity with IC50 values of less than 5 μM, which was more potent than the nonspecific NOS inhibitor Nω-nitro-L-arginine methyl ester (L-NAME).
doi:10.1021/np1002143
PMCID: PMC2993773  PMID: 21028898
20.  Antitumor Agents 280. Multidrug Resistance-Selective Desmosdumotin B Analogues 
Journal of medicinal chemistry  2010;53(18):6699-6705.
6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR–selective flavonoid with significant in vitro anticancer activity against a multi-drug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2-analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR–selectivity. Three new disubstituted analogues, 35, 37 and 49, also had high collateral sensitivity (CS) indices of 273, 250 and 100, respectively. Furthermore, 2–4 also displayed MDR-selectivity in an MDR hepatoma-cell system. While 2–4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.
doi:10.1021/jm100846r
PMCID: PMC2945214  PMID: 20735140
21.  Antitumor Agents 282. 2′-(R)-O-Acetylglaucarubinone, a Quassinoid from Odyendyea gabonensis as a Potential Anti-breast and Anti-ovarian Cancer Agent 
Journal of natural products  2010;73(9):1553-1558.
A new quassinoid, designated 2′-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2–8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre (Simaroubaceae)]. The structure of 1 was determined by spectroscopic analysis, and by semi-synthesis from glaucarubolone. Complete 1H and 13C NMR assignments of compounds 1–8 were also established from detailed analysis of two-dimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor (ER) or progesterone receptor (PR). When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.
doi:10.1021/np100406d
PMCID: PMC2954497  PMID: 20738103
22.  Antitumor Agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) Analogs as Potent In Vitro Anticancer Agents 
4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs were designed, synthesized, and evaluated for cytotoxic activity. Among all 4-substituted ABO analogs, cyclohexyl (12), N-methoxy-N-methylacetamide (14), and various aromatic derivatives (15-25 and 27) exhibited promising cell growth inhibitory activity with ED50 values of 0.01-2.1 μM against all tested tumor cell lines. The 4′-methoxyphenyl derivative (18) and 3′-methylphenyl derivative (24) showed the most potent antitumor activity against a broad range of cancer cell lines with ED50 values of 0.01-0.17 μM. Preliminary SAR results indicated that substitutions on nitrogen are critical to the antitumor potency.
doi:10.1016/j.bmcl.2010.05.079
PMCID: PMC2917187  PMID: 20542429
4-Amino-2H-benzo[h]chromen-2-one analogs (ABO); cytotoxic activity; structure-activity relationships
23.  Antitumor agents 273.† Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents 
As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC50 = 0.88 – 1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED50 values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.
doi:10.1016/j.bmcl.2010.05.081
PMCID: PMC2933066  PMID: 20542428
N-Alkylthiocolchinoids; Antitumor agents; Tubulin polymerization
24.  Cytotoxic Polyisoprenyl Benzophenonoids from Garcinia subelliptica 
Journal of natural products  2010;73(4):557-562.
Six new polyisoprenyl benzophenonoids, (±)-garcinialiptone A (1, 2), garcinialiptone B (3), (−)-cycloxanthochymol (4), garcinialiptone C (5), and garcinialiptone D (6), along with three known compounds, xanthochymol (7), isoxanthochymol (8), and cycloxanthochymol (9), were isolated from the fruits of Garcinia subelliptica. The structures of 1–6 were elucidated by spectroscopic analysis. Biological evaluation showed that all compounds 1–9 exhibited cytotoxic activity against a small panel of human tumor cell lines (A549, DU145, KB, vincristine-resistant KB).
doi:10.1021/np900620y
PMCID: PMC2860718  PMID: 20232858
25.  Antitumor Agents 274. A New Synthetic Strategy for E-ring SAR Study of Antofine and Cryptopleurine Analogs 
Organic letters  2010;12(7):1416-1419.
A new versatile synthetic methodology for the synthesis of enantiomerically pure natural phenanthroindolizidines and phenanthroquinolizidines has been established and described. Natural products R-antofine and R-cryptopleurine, as well as a novel E-ring expanded analog 13c (E7), 12-oxo-S-antofine (17), and 12N-methyl-12-aza-S-antofine (18) were synthesized with the new method. This strategy will greatly facilitate future SAR studies on the natural alkaloids with E-ring variations.
doi:10.1021/ol902819j
PMCID: PMC2849728  PMID: 20196574

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