Synthesis and cytotoxicity of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin.

Abstract

A series of 1,6,7,8-substituted 2-(4'-substituted phenyl)-4-quinolones and related compounds have been synthesized and evaluated as cytotoxic compounds and as antimitotic agents interacting with tubulin. The 2-phenyl-4-quinolones (22-30) with substituents (e.g. F, Cl, and OCH3) at C-6, C-7, and C-8 show, in general, potent cytotoxicity against human lung carcinoma (A-549), ileocecal carcinoma (HCT-8), melanoma (RPMI-7951), and epidermoid carcinoma of the nasopharynx (KB) and two murine leukemia lines (P-388 and L1210). Introduction of alkyl groups at N-1 or C-4 oxygen led to inactive compounds (35-43 and 50). In addition, compounds 24, 26, and 27 were evaluated in the National Cancer Institute's 60 human tumor cell line in vitro screen. These compounds demonstrated the most marked effects in the screen on two colon carcinoma cell lines (COLO-205 and KM-20L2) and on a central nervous system tumor cell line (SF-539) with compound 26 the most potent of the three agents. Compounds 24, 26, and 27 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. The three agents also inhibited the binding of radiolabeled colchicine to tubulin, but this inhibition was less potent than that obtained with the natural products.

• Authors: S C Kuo, H Z Lee, J P Juang, Y T Lin, T S Wu, J J Chang, D Lednicer, K D Paull, C M Lin, E Hamel
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 36 Issue 9 Pg. 1146-56 (Apr 30 1993) ISSN: 0022-2623 [Print] United States
• PMID: 8387598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Quinolines
• Quinolones
• Tubulin
• Tubulin Modulators
• 6-chloro-2-phenyl-4-quinolone
• 7-fluoro-2-phenyl-4-quinolone
• 6-methoxy-2-phenyl-4-quinolone

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Humans
• Intestinal Neoplasms (drug therapy)
• Leukemia L1210 (drug therapy)
• Leukemia P388 (drug therapy)
• Lung Neoplasms (drug therapy)
• Melanoma (drug therapy)
• Mice
• Molecular Structure
• Nasopharyngeal Neoplasms (drug therapy)
• Quinolines (chemical synthesis)
• Quinolones (chemical synthesis, therapeutic use)
• Software
• Structure-Activity Relationship
• Tubulin (metabolism)
• Tubulin Modulators
• Tumor Cells, Cultured