Synthesis of 8-chloro-benzo[c]quinolizin-3-ones as potent and selective inhibitors of human steroid 5alpha-reductase 1.
The synthesis of a series of differently substituted 8-chloro-benzo[c]quinolizin-3-ones, as potent and selective human steroid 5alpha-reductase type 1 inhibitors, has been accomplished by a four-step procedure based on the TiCl4-promoted tandem Mannich-Michael cyclization of 2-silyloxy-1,3-butadienes with N-t-Boc iminium ions from quinolin-2-ones. The presence on the benzo[c]quinolizinone nucleus of a methyl group and a double bond at positions 6 and 4-4a, respectively, as in compound 1d, gave rise to one of the most potent non-steroidal 5alphaR-1 inhibitors reported so far (IC50 = 14 nM).
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Dipartimento di Chimica Organica U. Schiff and Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, CNR, Università di Firenze, Italy. guarna@chimorg.unifi.it
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D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014025:Titanium / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D011807:Quinolizines; D015363:Quinolones; C081531:8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)quinolin-3(2H)-one; C025096:titanium tetrachloride; D014025:Titanium; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase