Design, synthesis, and cytotoxic activity of Michael acceptors and enol esters in the benzo[b]acronycine series. (9/17)

A series of 2-acyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7- ones (4-6) was prepared by treatment of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (+/-)-cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-b enzo[b]pyrano[3,2-h]acridin-7-ones (9, 10) or (+/-)-cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b ]pyrano[3,2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin -7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC50 values within the same range of magnitude as (+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b ]pyrano[3,2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.  (+info)

Synthesis and cytotoxic activity of acronycine analogues in the benzo[c]pyrano[3,2-h]acridin-7-one and naphtho[1,2-b][1,7] and [1,10]-phenanthrolin-7(14H)-one series. (10/17)

Condensation of 1-bromo-2-naphthalenecarboxylic acid (9) with 7-methoxy-2,2-dimethyl-2H-1-benzopyran-5-ylamine (13) followed by acid-mediated cyclization afforded 6-methoxy-3,3-dimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (15), which was further methylated into 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (benzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4). Osmium tetroxide oxidation of 15 gave the (+/-)-cis-diol 16, which afforded the benzopyranoacridine and benzopyranoacridone esters 17-22 upon acylation. Condensation of 9 with suitable aminoquinolines 23-25 afforded the carboxylic naphthylquinolylamines 26-28. Cyclization gave the corresponding naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-ones 29 and 30, and naphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one 31, which were subsequently N-methylated to the desired 14-methylnaphtho[1,2-b][1,10] and [1,7]-phenanthrolinones 6, 7, and 8. Benzo[c]pyrano[3,2-h]acridin-7-one derivatives 3, 16, and 22 displayed cytotoxic activities within the same range of magnitude as acronycine itself, whereas 7-alkoxybenzo[c]pyrano[3,2-h]acridine and 7-acyloxybenzo[c]pyrano[3,2-h]acridine derivatives 4 and 17-21 were less active when tested against L1210 murine leukemia cells in vitro. Naphthophenanthrolinones 6-8 were devoid of significant antiproliferative activity, but compounds 29-31 bearing no substituent on the nitrogen atom at position 14 were more potent.  (+info)

Generation of replication-dependent double-strand breaks by the novel N2-G-alkylator S23906-1. (11/17)

S23906-1, a new DNA alkylating agent that reacts with the exocyclic 2-NH2 group of guanine residues yielding monofunctional adducts, is currently under clinical evaluation in phase I trials. To investigate the mechanism of action of S23906-1, we compared parental KB-3-1 cells and KB/S23-500 cells that are 15-fold resistant to S23906-1. Cell death induced by 1 micromol/L S23906-1 in KB-3-1 cells was associated with their irreversible arrest in the G2-M phases of the cell cycle followed by apoptosis, whereas a proportion of the resistant KB/S23-500 cells were able to exit from the G2 arrest and divide, leading to a significantly lower rate of apoptosis. The attenuated apoptotic response was associated with decreased Chk2 protein phosphorylation, indicating that the DNA damage signaling pathways are more potently activated in the sensitive cells. However, similar rates of adduct formation and repair were measured in both cell lines. Exposure to S23906-1 induced a higher formation of DNA breaks, measured by the comet assay, in sensitive cells. In agreement, a histone H2AX phosphorylation assay revealed that S23906-1 induced double-strand breaks (DSB) in a dose- and time-dependent manner and that these were more persistent in the parental cells. These DSBs were found mainly in S-phase cells and inhibited by aphidicolin, suggesting that they are DNA replication-mediated DSBs. These results suggest that secondary DNA lesions play an important role in the cytotoxicity of this compound and make histone H2AX phosphorylation an attractive marker for monitoring the efficacy of S23906-1.  (+info)

Synthesis and cytotoxic activity of benzo[a]pyrano[3,2-h] and [2,3-i]xanthone analogues of psorospermine, acronycine, and benzo[a]acronycine. (12/17)

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (+/-)-cis-diols 16 and 17, which afforded the corresponding esters 18-21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.  (+info)

Synthesis and cytotoxic activity of dimeric analogs of acronycine in the benzo[b]pyrano[3,2-h]acridin-7-one series. (13/17)

Coupling of 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (6) with alpha,omega-diiodoalkanes of varying length under alkaline conditions gave dimers 7-10. Halogenated ethers 11-14, cyclization products 15-17, and compounds 18-22 were also isolated in small yield from the reaction mixtures. Compounds 7-10 were more potent than acronycine and benzo[b]acronycine in inhibiting L1210 cell proliferation. The length of the alkyl ether linkage between the two benzopyranoacridone units had a dramatic influence on the cytotoxic activity. Compound 9 (n=5) was the most active, with an IC(50) value against L1210 cells within the same range of magnitude as diacetate 5, currently under clinical development.  (+info)

Influence of the stereoisomeric position of the reactive acetate groups of the benzo[b]acronycine derivative S23906-1 on its DNA alkylation, helix-opening, cytotoxic, and antitumor activities. (14/17)

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Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906. (15/17)

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Protein recognition of the S23906-1-DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). (16/17)

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