Identification of Novel 4'--Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II.

C4 variation of 4'--demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells.

Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents.

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.

Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors.

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.

Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica.

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.

Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents.

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.

Antitumor agents 295. E-ring hydroxylated antofine and cryptopleurine analogues as antiproliferative agents: design, synthesis, and mechanistic studies.

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.

Antitumor agents. 293. Nontoxic dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.

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.

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 IC(50) values of 0.

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.

Antitumor agents. 289. Design, synthesis, and anti-breast cancer activity in vivo of 4-amino-2H-benzo[h]chromen-2-one and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogues with improved water solubility.

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.

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.

Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents.

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.

Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents.

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.

Cytotoxic geranylflavonoids from Bonannia graeca.

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.

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).

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.

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.

New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis.

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.

A unique P-glycoprotein interacting agent displays anticancer activity against hepatocellular carcinoma through inhibition of GRP78 and mTOR pathways.

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.

Antitumor agents 283. Further elaboration of desmosdumotin C analogs as potent antitumor agents: activation of spindle assembly checkpoint as possible mode of action.

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.

Antitumor agents. 284. New desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents.

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.

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 (ED(50) 1.

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 analogs, except 8, 9, and 25-27, displayed potent tumor cell growth inhibitory activity.

Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.

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 analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity.

Camphoratins A-J, potent cytotoxic and anti-inflammatory triterpenoids from the fruiting body of Taiwanofungus camphoratus.

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.

Antitumor Agents. 282. 2'-(R)-O-acetylglaucarubinone, a quassinoid from Odyendyea gabonensis as a potential anti-breast and anti-ovarian cancer agent.

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]. The structure of 1 was determined by spectroscopic analysis and by semisynthesis from glaucarubolone.