RESUMO
New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6â¯nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors.
Assuntos
Carbamatos/química , Inibidores da Protease de HIV/síntese química , Protease de HIV/genética , Sítios de Ligação , Carbamatos/farmacologia , Domínio Catalítico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células HEK293 , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , MutaçãoRESUMO
Anigopreissin A belongs to stilbene di- and oligomeric forms containing a benzofuran ring system whose biological activity is unknown. Recently, a completely protected Anigopreissin A - Permethylated Anigopreissin A - has been synthesized. We use MTT bioassay to assess Permethylated Anigopreissin A cytotoxicity in different human cell lines. Furthermore, fluorescence microscopy, caspase activity, real-time PCR and Western-blot methods are employed to evaluate apoptotic cell death pathway in liver cancer cells. Permethylated Anigopreissin A kills different types of human cancer cells but does not affect non-tumorigenic cells. The Permethylated Anigopreissin A concentration that causes 50% inhibition of liver tumor cells is 0.24µM. Hepatoma cells treated with Permethylated Anigopreissin A arrest their cell cycle in G1 phase. We also demonstrate that Permethylated Anigopreissin A-triggered cell death occurs by apoptosis. Decrease of the BCL2 expression levels, loss of the mitochondrial membrane potential, release of cytochrome c and increase of caspase 9 activity highlight a key role for mitochondria in Permethylated Anigopreissin A-induced apoptosis. Our study shows that Permethylated Anigopreissin A kills liver cancer cells through intrinsic apoptotic pathway.
Assuntos
Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estilbenos/farmacologia , Benzofuranos/química , Western Blotting , Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Metilação , Reação em Cadeia da Polimerase em Tempo Real , Estilbenos/químicaRESUMO
An effective ligand-free Suzuki coupling protocol to unite methyl (E)-4-bromobut-2-enoate with several arylboronic acids has been accomplished. Thus, a number of variously functionalized methyl 4-arylcrotonates have been achieved in high to excellent yields under mild conditions. This method enables the preparation of diverse aryl-substituted cores of HIV-1 protease inhibitors.
Assuntos
Ácidos Borônicos/química , Crotonatos/síntese química , Inibidores da Protease de HIV/síntese química , Catálise , Técnicas de Química Combinatória , Crotonatos/química , Crotonatos/farmacologia , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Humanos , Estrutura Molecular , Paládio/químicaRESUMO
The ability of two common protected forms of amines (carbamates and sulfonamides) to serve as directing groups in Ni-catalyzed Suzuki reactions has been exploited in the development of catalytic asymmetric methods for cross-coupling unactivated alkyl electrophiles. Racemic secondary bromides and chlorides undergo C-C bond formation in a stereoconvergent process in good ee at room temperature in the presence of a commercially available Ni complex and chiral ligand. Structure-enantioselectivity studies designed to elucidate the site of binding to Ni (the oxygen of the carbamate and of the sulfonamide) led to the discovery that sulfones also serve as useful directing groups for asymmetric Suzuki cross-couplings of racemic alkyl halides. To our knowledge, this investigation provides the first examples of the use of sulfonamides or sulfones as effective directing groups in metal-catalyzed asymmetric C-C bond-forming reactions. A mechanistic study established that transmetalation occurs with retention of stereochemistry and that the resulting Ni-C bond does not undergo homolysis in subsequent stages of the catalytic cycle.
Assuntos
Alcanos/química , Carbono/química , Elétrons , Níquel/química , Catálise , Estereoisomerismo , Especificidade por SubstratoRESUMO
Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC(50)=60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Tiofenos/síntese química , Antivirais/química , Inibidores da Protease de HIV/química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Tiofenos/química , Tiofenos/farmacologiaRESUMO
A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1H-indolyl)oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2-ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis.
RESUMO
A series of new thienyl ring containing analogues of nelfinavir and saquinavir with different substitution patterns were synthesized from suitable enantiopure diols. Their inhibitory activity against wild type recombinant HIV-1 protease was evaluated. In general thienyl groups spaced from the core by a methylene group gave products showing IC(50) in the nanomolar range, irrespective of the type and the substitution pattern of the heterocycle. The range of activity of the two most active compounds is substantially maintained or even increased against two commonly selected mutants, under drug pressure, such as V32I and V82A.