Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4 '-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles

Citation
Xk. Zhu et al., Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4 '-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles, J MED CHEM, 42(13), 1999, pp. 2441-2446
Citations number
18
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
0022-2623 → ACNP
Volume
42
Issue
13
Year of publication
1999
Pages
2441 - 2446
Database
ISI
SICI code
0022-2623(19990701)42:13<2441:AA1SAB>2.0.ZU;2-R
Abstract
As a continuation of our structure-activity relationship studies, several n ew 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inh ibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Se lected compounds were further evaluated as cytotoxic agents using a clonoge nic survival assay. The target compounds include 4'-O-demethyl-4 beta-[(4 " -(benzimidazol-2 " yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl- 4 beta-(-)-(4 "-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta- disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-a lpha-disubstitued-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta- trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O -demethyl-4 beta-[4 "-(benzimidazol-2 "-yl)amino]-4-desoxypodophyllotoxin ( 24). Among the target series, 19, 21, and 24 displayed significant growth i nhibitory action against a panel of tumor cell lines including human epider moid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) a nd vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), huma n ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast aden ocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compound s 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the proto type drug etoposide (VP-16). Compound 21 was the most active analogue, bein g 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 2 1 was effective against (P388/0) leukemia but not against the growth of a ( MCF7) mammary tumor.