Does structural commonality of metal complex formation by PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) denote mechanistic similarity? Signal transduction and medical aspects.
There is an urgent need of novel approaches to drugs in the cancer, HIV, and bacterial areas. Increasing resistance to conventional therapies is observed. This minireview provides novel insights for drugs in these three areas. The agents PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) have recently attracted attention due to considerable potential based on new approaches. PAC-1 activates procaspase-3 to caspase-3, resulting in induction of apoptosis in tumor cells. DHBNH binds to a newly revealed site on HIV reverse transcriptase. The drug mainly inhibits RNase H (RNA-cleaving). AHLs comprise an important class that participates in bacterial cell communication. UCS1025A is a fungus-derived inhibitor of the enzyme telomerase, present in cancer cells, which is crucially involved in tumor cell immortality. All four agents possess chelating sites for metal binding, which has not been appreciated. In PAC-1 and DHBNH, the coordinating portion is similar to salicylaldehyde semicarbazone. For AHL and UCS1025A, the metal-binding moiety is a beta -ketoamide. Metal complexes of heavier metals are well-known electron transfer (ET) functionalities that can generate reactive oxygen species. Hence, it is reasonable to hypothesize a commonality in mechanism based on metal ET. Differences in receptor binding can result, in part, in diverse physiological responses. There is considerable literature that addresses involvement of signal transduction with the various physiologically active agents discussed herein. Thus, cell communication appears to play an important role in the biochemistry of these endogenous and exogenous substances. Details of cell signaling are presented for complexes of metals (Fe, Cu, Ni, and As), telomerase, caspase-3, and RNase. In addition, practical medical aspects are discussed.
Department of Chemistry, San Diego State University, San Diego, California 92182-1030, USA. pkovacic@sundown.sdsu.edu
Peter
P
Kovacic
D054742:Acyl-Butyrolactones / Q000737:chemistry*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry*; D008670:Metals / Q000378:metabolism*; D009281:Naphthalenes / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry*; D015398:Signal Transduction
C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D054742:Acyl-Butyrolactones; D019380:Anti-HIV Agents; D006835:Hydrazones; D008670:Metals; D009281:Naphthalenes; D010879:Piperazines; D011763:Pyrrolizidine Alkaloids; C409195:UCS 1025A; C532097:dihydroxy benzoyl naphthyl hydrazone