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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.

Abstract
As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.
AuthorsX K Zhu, J Guan, Y Tachibana, K F Bastow, S J Cho, H H Cheng, Y C Cheng, M Gurwith, K H Lee
JournalJournal of medicinal chemistry (J Med Chem) Vol. 42 Issue 13 Pg. 2441-6 (Jul 01 1999) ISSN: 0022-2623 [Print] United States
PMID10395485 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 4'-O-demethyl-4-(4''-(benzimidazol-2''-yl)anilino)-4-desoxypodophyllotoxin
  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Topoisomerase II Inhibitors
  • Etoposide
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Benzimidazoles (chemical synthesis, chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Etoposide (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Leukemia P388 (drug therapy)
  • Mammary Neoplasms, Experimental (drug therapy)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured

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