RESUMO
Tyrosine kinase inhibitors (TKIs) provide more effective targeted treatments for cancer, but are subject to a variety of adverse effects, such as hypothyroidism. TKI-induced hypothyroidism is a highly complicated issue, because of not only the unrealized toxicological mechanisms, but also different incidences of individual TKI drugs. While sunitinib is suspected for causing thyroid dysfunction more often than other TKIs, sorafenib is believed to be less risky. Here we integrated clinical data and in silico drug-protein interactions to examine the pharmacological distinction between sunitinib and sorafenib. Statistical analysis on the FDA Adverse Event Reporting System (FAERS) confirmed that sunitinib is more concurrent with hypothyroidism than sorafenib, which was observed in both female and male patients. Then, we used docking method and identified 3 proteins specifically binding to sunitinib but not sorafenib, i.e., retinoid X receptor alpha, retinoic acid receptors beta and gamma. As potential off-targets of sunitinib, these proteins are well known to assemble with thyroid hormone receptors, which can explain the profound impact of sunitinib on thyroid function. Taken together, we established a strategy of integrated analysis on clinical records and drug off-targets, which can be applied to explore the molecular basis of various adverse drug reactions.
Assuntos
Hipotireoidismo/induzido quimicamente , Indóis/química , Indóis/farmacologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Pirróis/química , Pirróis/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Hipotireoidismo/epidemiologia , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Niacinamida/efeitos adversos , Niacinamida/química , Niacinamida/farmacologia , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirróis/efeitos adversos , Receptores do Ácido Retinoico/metabolismo , Receptor X Retinoide alfa/metabolismo , Sorafenibe , Sunitinibe , Receptor gama de Ácido RetinoicoRESUMO
Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC(50) value of 0.058 microM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC(50): 0.126 microM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate.
Assuntos
Fármacos Anti-HIV/síntese química , Cumarínicos/química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Cumarínicos/síntese química , Cumarínicos/farmacologia , Desenho de Fármacos , Humanos , Conformação MolecularRESUMO
The title compound, C(13)H(13)NO(2)S, was prepared by a thermocyclization reaction from 3-methyl-6-(2-methyl-but-3-yn-2-yl-oxy)benzo[d]thia-zol-2(3H)-one. In the crystal structure, the methyl-thia-zole unit is planar, while the pyran ring assumes a screw-boat conformation. Intra-molecular C-Hâ¯O hydrogen bonding helps to stabilize the molecular structure.
RESUMO
Two thia-DCK analogs (3a,b) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Compound 3a showed potent anti-HIV activity with an EC50 value of 0.14 microM and a therapeutic index of 1110. However, the corresponding 6-tert-butyl-substituted compound (3b) showed no suppression. The bioassay results indicated that thia-DCK analogs merit attention as potential HIV-1 inhibitors.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , HIV/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lactonas/síntese química , Lactonas/farmacologia , Linfócitos/virologia , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/farmacologiaRESUMO
Two 1-thia-DCK analogues (9a and 9b) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Compound 9a showed excellent anti-HIV activity with an EC(50) value of 0.00012 microM and therapeutic index of 1408000. Compound 9b was less active with EC(50) and TI values of 3.11 microM and 62.3, respectively. The bioassay results indicated that thia-DCK analogues merit attention as potential HIV-1 inhibitors.