Synthetic DNA minor groove-binding drugs

In this review, both cationic and neutral synthetic ligands that bind in th e minor groove of DNA are discussed. Certain bis-distamycins and related le xitropsins show activities against human immunodeficiency virus (HIV)-1 and HIV-2 at low nanomolar concentrations. DAPI binds strongly to AT-containin g polymers and is located in the minor groove of DNA. DAPI intercalates in DNA sequences that do not contain at least three consecutive AT bp. Berenil can also exhibit intercalative, as well as minor groove binding, propertie s depending on sequence. Furan-containing analogues of berenil play an impo rtant role in their activities against Pneumocystis carinii and Cryptospori dium parvuam infections in vivo. Pt(II)-berenil conjugates show a good acti vity profile against HL60 and U-937 human leukemic cells. Pt-pentamidine sh ows higher antiproliferative activity against small cell lung, non-small ce ll lung, and melanoma cancer cell lines compared with many other tumor cell lines. trans-Butenamidine shows good anti-P. carinii activity in rats. Pen tamidine is used against P. carinii pneumonia in individuals infected with HIV who are at high risk from this infection. A comparison of the cytotoxic potencies of adozelesin, bizelesin, carzelesin, cisplatin, and doxorubicin indicates that adozelesin is a potent analog of CC-1065. Naturally occurri ng pyrrolo[2,1-c][1,4]benzodiazepines such as anthramycin have a 2- to 3-bp sequence specificity, but a synthetic PBD dimer spans 6 bp, actively recog nizing a central 5'-GATC sequence. The crosslinking efficiency of PBD dimer s is much greater than that of other major groove crosslinkers, such as cis platin, melphalan, etc. Neothramycin is used clinically for the treatment o f superficial carcinoma of the bladder. (C) 1999 Elsevier Science Inc. All rights reserved.