Synthesis and preliminary biological evaluations of CC-1065 analogues: effects of different linkers and terminal amides on biological activity.
CC-1065 analogues possessing a biologically active CBI functional group and amide-substituted indole and benzofuran were synthesized. The IC(50) values of compounds 26, bearing two indoles, and 25, bearing only one indole, are 0.4 and 3 nM, respectively, against U937 leukemia cells in vitro. The IC(50) values of compounds 28, bearing a butyramino group, and 27, bearing an acetamino group, are 0.008 and 0.4 nM, respectively, against U937 leukemia cells in vitro. Compound 29, bearing a double-bond linker, is about 4-fold more potent than 25, bearing no double-bond linker. Compound 26 is highly potent against all cell lines tested in the NCI in vitro screening with IC(50) values in the 0.1-5 nM range for most cell lines. Compounds 26 and 30 are highly active against L1210 leukemia in mice. Compound 26 is also active against B16BL6 melanoma in mice. Most importantly, 26 and 30 are not myelosuppressive at therapeutically effective doses. The mechanism of tumor cell death is through induction of apoptosis, and is accompanied by DNA fragmentation.
Wang
Y
Y
Panorama Research, Inc., 2462 Wyandotte Street, Mountain View, California 94043, USA. Yuqiang@worldnet.att.net
Yuan
H
H
Ye
W
W
Wright
S C
SC
Wang
H
H
Larrick
J W
JW
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007933:Leucomycins / Q000737:chemistry*; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010976:Platelet Count / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C407513:2-((5-((5-acetamino-1H-benzofuran-2-ylcarbonyl)amino)-1H-indol-2-yl)carbonyl)-1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; C407512:3-((5-((5-acetamino-1H-indol-2-ylcarbonyl)amino)-1H-indol-2-yl)carbonyl)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz(e)indole; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001572:Benzofurans; D000080890:Duocarmycins; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D007933:Leucomycins; C018782:CC 1065; D004247:DNA