Hui Kang Wang

Antitumor agents. Part 214: synthesis and evaluation of curcumin analogues as cytotoxic agents.

Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and <0.63 microg/mL, respectively.

Antitumor agents 201.1 Cytotoxicity of harmine and β-carboline analogs

Twenty-six beta-carbolines were evaluated for in vitro cytotoxicity in a human tumor cell line panel. Harmine (3) showed significant activity against several cell lines including three drug-resistant KB sublines with various resistance mechanisms. Alpha-(4-nitrobenzylidine) harmine (16) had a broad cytotoxicity spectrum (ED50 values from 0.3-1.2 microg/mL against 1A9, KB, SaOS-2, A549, SK-MEL-2, U-87-MG, and MCF-7 cells).

Synthesis and anti-HIV activity of oleanolic acid derivatives

Thirteen oleanolic acid derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Saturating the C(12)-C(13) double bond and converting the C(17)-carboxyl group to an aminomethyl group led to compounds 13-15 and 19-20, respectively, which showed improved anti-HIV activity. Compound 15 was the most potent derivative with EC(50)=0.0039 microg/mL and TI=3570.

Antitumor-promoting effects of cyclic diarylheptanoids on Epstein-Barr virus activation and two-stage mouse skin carcinogenesis

Eleven cyclic diarylheptanoids were screened as potential antitumor promoters by examining the ability of the compounds to inhibit Epstein-Barr virus early antigen activation (induced by 12-O-tetradecanoylphorbol-13-acetate) in Raji cells. 13-Oxomyricanol and myricanone showed the highest activity and also exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. These data suggest that certain diarylheptanoids might be valuable antitumor promoters and/or chemopreventors.

Antitumor agents—CLXXIII. Synthesis and evaluation of camptothecin-4β-amino-4′-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents☆

Two conjugates composed of a camptothecin and a 4-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells.

Antitumor agents 210. Synthesis and evaluation of taxoid-epipodophyllotoxin conjugates as novel cytotoxic agents

Five compounds composed of a taxoid (paclitaxel or cephalomannine) and a 4-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as cytotoxic agents and inhibitors of mammalian DNA topoisomerase II. Compounds 12 and 14-16 exhibited comparable or better activity than the unconjugated epipodophyllotoxin derivatives in most tumor cell lines, and 12, 15, and 16 also showed enhanced activity against paclitaxel-resistant cells. Compound 13, which contains an epipodophyllotoxin moiety at both the taxoid 2 and 7 positions, did not stimulate protein-DNA breaks, but was 2-fold more potent than 12 and 15 and comparable to GL-331 in the topo II inhibitory assay.

Antitumor agents. Part 209: Pheophorbide-a derivatives as photo-Independent cytotoxic agents.

A methanolic crude extract of the plant Garuga pinnata Roxb. (Burseraceae) showed promising cytotoxic activity against a panel of human tumor cell lines in vitro, including KB and its drug-resistant sublines (Ferguson et al. Cancer Res. 1988, 48, 5956). Pheophorbide-a and-b methyl esters (3,4) were isolated as active principles with broad photo-dependent cytotoxic activities in the micromolar range. These findings prompted SAR studies of known and novel pheophorbide-a derivatives as photo-dependent and photo-independent cytotoxic agents. The results showed that zinc-protoporphyrin IX (10), zinc 13(R)-hydroxypheophorbide-a methyl ester (22), and zinc chlorin-e6 trimethyl ester (13) possessed photo-independent cytotoxic activity. Compounds 13 and 22 were the most active cytotoxic agents of the series (mean ED(50) 4.6 +/- 1.0 microM and 5.7 +/- 0.7 microM, respectively) against KB cells incubated in the dark.

Antitumor agents. 1771. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors

Abstract Novel water-soluble 4 β -amino-4′- O -demethylepipodophyllotoxin derivatives (6–12) , designed to enhance minor groove binding ability, were synthesized and screened against NCIs in vitro disease-oriented human tumor cells. Among them, 4′- O -demethyl-4 β -[ N -(1‴-methyl-4‴-nitro-pyrrole-2‴-carbonyl)-4″-aminoanilino]-4-desoxypodophyllotoxin ( 10 ) and its HCl salt ( 11 ) were found to exhibit potent cytotoxic activities (average log GI 50 = −6.91, −7.00, and −5.01 for 10 , 11 , and etoposide, respectively). Compounds 10 and 12 were further tested for their inhibitory activities against DNA topoisomerase II. Compound 10 again exhibited a superior activity profile compared to that of etoposide, displaying increased cytotoxicity against KB and KB-7d cells ( ID 50 LD 50 = 0.04 0.15 and 0.2 0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 μM), and cellular protein DNA complex formation (225%).

Synthesis of novel water-soluble 7-(aminoacylhydrazono)-formyl camptothecins with potent inhibition of DNA topoisomerase I☆

Eighteen new water-soluble 7-(aminoacylhydrazono)-formyl camptothecins were synthesized and evaluated for their ability to cause protein-linked DNA breaks and to inhibit topoisomerase I activity. Compared with camptothecin, five of the compounds were as potent or more potent in these tw assays but were less toxic in several cancer cell lines. The results suggest that the 7 position in the B ring is a suitable location for introducing a polar moiety into camptothecin producing analogues with enhanced topoisomerase I inhibiting activity.

The synthesis of 5-substituted camptothecins as potential inhibitors of DNA topoisomerase I

Four new 5-substituted camptothecins (4–7) have been synthesized and evaluated for DNA topoisomerase I inhibition. The results suggested that the pyridone moiety in the D ring of camptothecin plays a crucial role in determining its activity and that the 5 position of the C ring should be unsubstituted for retention of activity.