-
[show abstract]
[hide abstract]
ABSTRACT: 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, KB(VIN), and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC(50) 1.4-1.7μM) 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.
Bioorganic & medicinal chemistry 12/2012; · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 EC(50) values of 4.9, 0.8, 3.4, and 3.2 μg/mL, respectively.
Journal of Natural Products 10/2012; · 3.13 Impact Factor
-
Xiao-Feng Wang,
Xing-Tao Tian,
Emika Ohkoshi,
Bingjie Qin,
Yi-Nan Liu,
Pei-Chi Wu,
Mann-Jen Hour,
Hsin-Yi Hung,
Keduo Qian,
Rong Huang, Kenneth F Bastow,
William P Janzen,
Jian Jin,
Susan L Morris-Natschke,
Kuo-Hsiung Lee,
Lan Xie
[show abstract]
[hide abstract]
ABSTRACT: Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
Bioorganic & medicinal chemistry letters 08/2012; 22(19):6224-8. · 2.65 Impact Factor
-
Xiaoming Yang,
Qian Shi,
Chin-Yu Lai,
Chi-Yuan Chen,
Emika Ohkoshi,
Shuenn-Chen Yang,
Chih-Ya Wang, Kenneth F Bastow,
Tian-Shung Wu,
Shiow-Lin Pan,
Che-Ming Teng,
Pan-Chyr Yang,
Kuo-Hsiung Lee
[show abstract]
[hide abstract]
ABSTRACT: Various E-ring hydroxylated antofine and cryptopleurine analogues 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 nonsmall 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.
Journal of Medicinal Chemistry 07/2012; 55(15):6751-61. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Novel dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) analogues were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells, a multidrug resistant cell line overexpressing 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. Analogue 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogues against both non-MDR and MDR cells, suggesting that DDB analogues serve as novel lead compounds for the development of chemosensitizers to overcome the MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogues dramatically elevated the cellular concentration of anticancer drugs.
Journal of Medicinal Chemistry 05/2012; 55(11):5413-24. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 IC(50) values of 0.9 and 0.8 μg/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.
Bioorganic & medicinal chemistry letters 04/2012; 22(12):4018-22. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 03/2012; 22(9):3219-22. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 product 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 IC(50) 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 a mouse model of human breast cancers. Compound 10 merits further development as a promising anticancer clinical trial candidate.
Journal of Natural Products 02/2012; 75(3):370-7. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Medicinal chemistry. 12/2011; 1(101).
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Bioorganic & medicinal chemistry letters 11/2011; 22(1):249-52. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Chalcones have a distinctive 1,3-diarylpropenone skeleton and exert numerous biological effects. Using a one-step Claisen-Schmidt condensation, we synthesized eleven bis-chalcones (3-13) and three acetyl chalcones (14-16) from substituted aldehydes and diacetylresorcinol. The compounds were tested for in vitro cytotoxic activity against four human cancer cell lines (A549, DU145, KB, and KB-VIN) and inhibition of NO production in lipopolysaccharide (LPS)-activated microglial cells. Among them, four compounds (3, 5, 6, and 13) showed significant cytotoxic activity with EC(50) values ranging from 1.57 to 5.14 μM, and seven compounds (3, 5-8, 10, and 13) displayed potent anti-inflammatory activity by inhibiting NO production with IC(50) values ranging from 0.95 to 8.65 μM. A mechanism of action study of active compounds 6 and 7 discovered that these compounds down-regulated iNOS expression by inhibiting p65 NF-κB activation/nuclear translocation due to prevention of IκBα degradation. Structure-activity relationship (SAR) findings are also discussed.
European journal of medicinal chemistry 10/2011; 47(1):97-103. · 3.27 Impact Factor
-
Xiaoming Yang,
Qian Shi,
Shuenn-Chen Yang,
Chi-Yuan Chen,
Sung-Liang Yu, Kenneth F Bastow,
Susan L Morris-Natschke,
Pei-Chi Wu,
Chin-Yu Lai,
Tian-Shung Wu,
Shiow-Lin Pan,
Che-Ming Teng,
Jau-Chen Lin,
Pan-Chyr Yang,
Kuo-Hsiung Lee
[show abstract]
[hide abstract]
ABSTRACT: Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.
Journal of Medicinal Chemistry 06/2011; 54(14):5097-107. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The analysis of the aerial parts of Bonannia graeca led to the isolation and characterization of 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.
Phytochemistry 04/2011; · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 IC(50) 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 GI(50) values ranging from 0.70 to 13.10 μM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling.
Bioorganic & medicinal chemistry 03/2011; 19(6):1895-906. · 2.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 var. major. 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 IC(50) values ranging from 0.78 to 43.6 μM. In addition, 1 showed greater than 2- to 3-fold selective cytotoxic activity against KB and DU145 cancer cell lines.
Journal of Natural Products 03/2011; 74(4):796-802. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 ED(50) values of 0.059-0.090 μM.
Bioorganic & medicinal chemistry letters 03/2011; 21(8):2341-4. · 2.65 Impact Factor
-
Kyoko Nakagawa-Goto,
Pei-Chi Wu,
Chin-Yu Lai,
Ernest Hamel,
Hao Zhu,
Liying Zhang,
Takashi Kozaka,
Emika Ohkoshi,
Masuo Goto, Kenneth F Bastow,
Kuo-Hsiung Lee
[show abstract]
[hide abstract]
ABSTRACT: 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 GI(50) 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 resistant 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 GI(50) 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.
Journal of Medicinal Chemistry 02/2011; 54(5):1244-55. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: P-glycoprotein (P-gp) overexpression has been demonstrated in many malignancies being a predominant mechanism by which cancer cells develop multidrug resistance. Several categories of P-gp inhibitors have been demonstrated to potentiate anticancer effect induced by cancer chemotherapeutic drugs through competitive inhibition of P-gp pumping activity. Few studies show the agent that selectively acts on P-gp and, by itself, causes cell apoptosis while remain P-gp-deficient cells unaffected. KNG-I-322, a desmosdumotin B derivative, displayed a direct interaction with P-gp and demonstrated selective anti-proliferative and apoptotic activities in P-gp overexpressed Hep3B/VIN other than P-gp-deficient Hep3B cells. KNG-I-322 induced an inhibitory effect on the phosphorylation of mTOR(Ser2448), p70S6K(Thr389) and 4E-BP(Thr37/46) in Hep3B/VIN but not Hep3B cells. The inhibition was fully blocked by the knockdown of P-gp using siRNA techniques. Notably, the P-gp inhibitor, verapamil, also directly interacted with P-gp but significantly diminished KNG-I-322-induced anti-proliferative activity. After the mechanism study, the data showed that KNG-I-322 induced a dramatic down-regulation of GRP78 expression, which was significantly inhibited by verapamil and completely diminished by the knockdown of P-gp. The protein profile analysis of detergent resistant membranes showed that upon the stimulation by KNG-I-322, the level of P-gp expression in non-raft fractions was dramatically increased and, concomitantly, the GRP78 expression was significantly decreased. Taken together, the data suggest that KNG-I-322 induces anticancer activity in Hep3B/VIN cells through a direct interaction with P-gp, leading to the inhibition of mTOR pathways and the induction of GRP78 down-regulation. The data support that KNG-I-322 is a selective anticancer agent against P-gp-overexpressed other than P-gp-deficient cancer cells.
Biochemical pharmacology 02/2011; 81(9):1136-44. · 4.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 (ED(50) 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 (ED(50) 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED(50) 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 Brca1(f11/f11)p53(f5&6/f5&6)Cre(c) mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands.
Bioorganic & medicinal chemistry letters 01/2011; 21(1):52-7. · 2.65 Impact Factor
-
Kyoko Nakagawa-Goto,
Pei-Chi Wu, Kenneth F Bastow,
Shuenn-Chen Yang,
Sung-Liang Yu,
Hsuan-Yu Chen,
Jau-Chen Lin,
Masuo Goto,
Susan L Morris-Natschke,
Pan-Chyr Yang,
Kuo-Hsiung Lee
[show abstract]
[hide abstract]
ABSTRACT: 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 ED(50) 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 (ED(50) 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.
Bioorganic & medicinal chemistry 01/2011; 19(5):1816-22. · 2.82 Impact Factor
