- Cytotoxic α-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety
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The design, synthesis, in vitro and in vivo activities of novel α-bromoacrylic derivatives of distamycin A, modified at the amidino moiety by the replacement with basic or non-basic groups are reported. In spite of the relevance of these modifications of distamycin frame, the new derivatives are potent cytotoxics. The presence of the amidino moiety, is, therefore, not an absolute requirement for the activity. In particular due to a favorable myelotoxicity/cytotoxicity ratio, guanidino derivative PNU 166196 was selected for clinical development. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Cozzi, Paolo,Beria, Italo,Caldarelli, Marina,Geroni, Cristina,Mongelli, Nicola,Pennella, Giulia
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p. 1273 - 1276
(2007/10/03)
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- Synthesis and antiviral activity of distamycin A analogues: Substitutions on the different pyrrole nitrogens and in the amidine function
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Several new analogues of the antiviral antibiotic distamycin A were synthesized and assayed for their effects on influenza and herpes simplex virus. The new compounds 5b-j (R1-3 = H, CH3, and C2H5, R(4,5) = H and CH3) were obtained via stepwise prepared formylated trimeric benzyl 4-aminopyrrole-2-carboxylates 3a-h, which after catalytic hydrogenolysis were coupled as N-succinimidyl esters directly with the proper β-aminopropionamidine, unsubstituted or substituted with one or two methyl groups in the aminidine function. Most of the new analogues did not exhibit significant effects on the viruses studied, but three compounds (5f-h) displayed activity on herpes virus as demonstrated in plaque formation and virus yield assays. Elevated cytotoxicity was simultaneously observed for 5g and 5h. For compound 5f, a partial separation of antiherpes activity and cytotoxicity was accomplished. The differences in antiherpes activity did not correspond to the differences in the inhibition of herpes virus DNA polymerase.
- Grehn,Ragnarsson,Eriksson,Oberg
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p. 1042 - 1049
(2007/10/02)
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