Design,Svnthesis And Preliminarv Biological Evaluation Of Some New Bile Acid Derivatives

Bile acids are endogenous natural steroidal products with extensive biological activities, and their derivatives possess high potential value in medicinal application. On the base of our group’s previous work, this dissertation focused on diverse modification on 4,4-dimethyl bile acid derivative 2-7 to develop high potent and selective bile acid derivatives. Two series of novel structural bile acid derivatives as well as a series with new scaffold were designed, synthesized and characterized with the application of drug molecular design strategy, and their inhibitory activities on PTP1B and cancer cell lines were evaluated, respectively. The work contained three parts:1) The 4,4-dimethyl bile acid derivative 2-7 were synthesized from LCA through six steps. Afterwards, based on the pharmacophore combination principal, amino group was introduced in C-3, followed by introduction of diverse functional groups through amide linkage. Twenty-four new 3-amino(amido)-4,4-dimethyl bile acid derivatives were synthesized and characterized, and their inhibitory activities on PTP1B enzyme were evaluated. The results showed that the inhibitory activities of most 3-amino(amido)-4,4-dimethyl bile acid derivatives on PTP1B were unsatisfactory, but compound 2-30 and 2-35, with imidazole and tryptophane linked to C-3 through amide, respectively, presented 4-fold improved potency on PTP1B compared to LCA (IC50=12.74 μM), with the ICso value of 3.81 and 3.36 μM, respectively. This indicated that introduction of aryl group in A ring may improve the activity.2) Twenty-five 2,3-pyrazole ring-substituted-4,4-dimethyl bile acid derivatives were synthesized and characterized with Knorr cyclocondensation reaction as the key step. HMBC and X-ray crystallography were used to analysis and ascertain the structures. Their inhibitory activities on PTP1B and selectivity over other homologous enzymes were evaluated to study the S AR. The most potent compound 2-70 exhibited 30-fold improved activity compared to nature bile acid with IC50 value of 0.42 μM; compound 2-67 and 2-76 presented more than 43-fold selectivity over TCPTP. Moreover, compound 2-70 and 2-79 showed cellular efficacy on PTP1B and thus improved the insulin sensitivity. We also investigated the enzyme kinetics and molecular docking analysis as well as the pharmacokinetic property.3) We optimized the synthetic route to yield compound 2-7 in a larger scale. Afterwards, thirty-three 3,4-seco bile acid derivatives containing amide groups were synthesized as new compounds with novel scaffold, and their antiproliferative activities against PC3M (prostate), HT29 (colon) and ES-2 (ovarian) cancer cell lines were investigated. The structure-activity relationship study showed that the most active compound was among the most antiproliferative bile acid derivatives, of which the IC50 value on PC3M cell was 1.07 μM with good selectivity on normal cell. Compound 3-42 could inhibit PC3M cell colony formation and cell migration in a dose-dependent manner, the mechanism study revealed that 3-42 induced PC3M cell cycle arrest at G1 phase.In summary, eighty-two bile acid derivatives were designed, synthesized and characterized as new compounds, and the SAR was studied. Among them,2-70 was identified as the most active PTP1B inhibitor and 3-42 exhibited good antiproliferative on PC3M cancer cell. These findings would lay a foundation for the drug discovery derivated from bile acids for the treatment of diabetes, obesity and cancer.