Synthetic DNA minor groove-binding drugs.
In this review, both cationic and neutral synthetic ligands that bind in the minor groove of DNA are discussed. Certain bis-distamycins and related lexitropsins show activities against human immunodeficiency virus (HIV)-1 and HIV-2 at low nanomolar concentrations. DAPI binds strongly to AT-containing 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, properties depending on sequence. Furan-containing analogues of berenil play an important role in their activities against Pneumocystis carinii and Cryptosporidium parvuam infections in vivo. Pt(II)-berenil conjugates show a good activity profile against HL60 and U-937 human leukemic cells. Pt-pentamidine shows higher antiproliferative activity against small cell lung, non-small cell lung, and melanoma cancer cell lines compared with many other tumor cell lines. trans-Butenamidine shows good anti-P. carinii activity in rats. Pentamidine 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 occurring pyrrolo[2,1-c][l,4]benzodiazepines such as anthramycin have a 2- to 3-bp sequence specificity, but a synthetic PBD dimer spans 6 bp, actively recognizing a central 5'-GATC sequence. The crosslinking efficiency of PBD dimers is much greater than that of other major groove crosslinkers, such as cisplatin, melphalan, etc. Neothramycin is used clinically for the treatment of superficial carcinoma of the bladder.
Reddy
B S
BS
Department of Chemistry, University of Alberta, Edmonton, Canada.
Sondhi
S M
SM
Lown
J W
JW
D000818:Animals; D001483:Base Sequence; D002986:Clinical Trials as Topic; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D004247:DNA