RESUMEN
The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Depsipéptidos/síntesis química , Depsipéptidos/farmacología , Anhídridos/química , Antineoplásicos/química , Depsipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Conformación Molecular , Estructura Molecular , Nitrobenzoatos/química , Resonancia Magnética Nuclear Biomolecular , Células Tumorales CultivadasRESUMEN
Three advances necessary to bring dolastatin 16 (1) into full-scale preclinical development as an anticancer drug have been accomplished. The X-ray crystal structure of dolastatin 16 has been solved, which allowed stereoselective syntheses of its two new amino acid units, dolamethylleuine (Dml) and dolaphenvaline (Dpv), to be completed. The X-ray crystal structures of synthetic Z-Dml and TFA-Dpv have also been completed.
Asunto(s)
Antineoplásicos , Depsipéptidos , Antineoplásicos/química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Depsipéptidos/síntesis química , Depsipéptidos/química , Depsipéptidos/farmacología , Estructura MolecularRESUMEN
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.