6-Alkylamino- and 2,3-dihydro-3'-methoxy-2-phenyl-4-quinazolinones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.
As part of our continuing search for potential anticancer candidates among 2-phenyl-4-quinolones and 2-phenyl-4-quinazolinones, two series of 6,7,2',3',4',5'-substituted 2-phenyl-4-quinazolinones and 6,2',3',4',5'-substituted 2,3-dihydro-2-phenyl-4-quinazolinones were synthesized and evaluated for cytotoxicity and as inhibitors of tubulin polymerization. In general, a good correlation was found between the two activities. Five of the 6-substituted heterocyclic 2-phenyl-4-quinozolinones (37-51) showed significant cytotoxicity against a panel of human tumor cell lines with EC(50) values in the low micromolar to nanomolar concentration ranges. Compound 38 was the most potent of these compounds, as well as the most potent inhibitor of tubulin polymerization in this series. The activity of 38 was in the same range as those of the antimitotic natural products, colchicine, podophyllotoxin, and combretastatin A-4. Substituted 2-phenyl-4-quinazolinones and 2, 3-dihydro-2-phenyl-4-quinazolinones also displayed highly selective cytotoxicity against the ovarian cancer 1A9 and P-gp resistant KB-VIN cell lines.
Hour
M J
MJ
Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung, Taiwan.
Huang
L J
LJ
Kuo
S C
SC
Xia
Y
Y
Bastow
K
K
Nakanishi
Y
Y
Hamel
E
E
Lee
K H
KH
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D052999:Quinazolinones; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
C416653:2-(3'-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone; D000970:Antineoplastic Agents; D001704:Biopolymers; D011759:Pyrrolidines; D011799:Quinazolines; D052999:Quinazolinones; D014404:Tubulin; D050257:Tubulin Modulators