3,6,19-Trihydroxy-23-oxo-12-ursen-28-oic acid

Breastmilk with a high omega-6 to omega-3 fatty acid ratio induced cellular events similar to insulin resistance and obesity in 3T3-L1 adipocytes.[Pubmed:28335075]

Pediatr Obes. 2018 May;13(5):285-291.

BACKGROUND: An imbalance of omega (n)-3 and n-6 polyunsaturated fatty acids (PUFA) during critical periods of development may have adverse effects on the health of the newborn in later life. OBJECTIVES: We hypothesized that breastmilk with higher n-6 to n-3 PUFA ratio will have higher inflammatory cytokines and initiate cellular events similar to insulin resistance and obesity. METHODS: Breastmilk was collected from healthy women who gave natural birth at full term. Breastmilk fatty acids were measured using gas chromatography; samples were pooled based on the n-6 to n-3 PUFA ratio (high, medium and low), and soluble cytokines were measured. Pooled samples were used to treat 3T3-L1 cells; mRNA expression of diacylglycerol acyltransferase2, stearoyl-CoA desaturase-1, leptin and RPLPO was measured. RESULTS: Breastmilk with a higher ratio of n-6 to n-3 PUFA showed higher pro-inflammatory cytokines; there was a direct correlation between n-6 PUFA and pro-inflammatory cytokines. Breastmilk with a higher ratio of n-6 to n-3 PUFA increased the expression of genes involved in lipogenesis. CONCLUSIONS: Pro-inflammatory cytokines in breastmilk are associated with higher levels of n-6 PUFA in breastmilk and has the capacity to alter adipose tissue metabolism to likely predispose the newborn to a higher risk of obesity in later life.

Design, Synthesis and Molecular Docking of 1-Cyclopropyl-6- Fluoro-4-Oxo-7-{4-[2-(4-Substituted-Phenyl)-2-(Substituted)-Ethyl] -1-Piperazinyl}-1,4-Dihydroquinoline-3-Carboxylic Acid as an Antimicrobial Agents.[Pubmed:28240185]

Curr Drug Discov Technol. 2017;14(4):255-269.

BACKGROUND: Quinolone scaffolds are widely used for the synthesis of a number of medicinal compounds with variety of biological activity. In view of the reported antimicrobial activity of various fluoroquinolones, the structure activity studies of various substituted quinolones, which proved the importance of the C-7 substituents to exhibit potent antimicrobial activities. OBJECTIVE: Based on the structural activity relationship at C-7 position it was rationalized to design and synthesize new quinolone derivatives with increasing bulk at C-7 position of the main 6-fluoroquinolone scaffold. METHODS: A novel series of 1-cyclopropyl-6-fluoro-4-oxo-7-{4-[2-(4-substituted-phenyl)- 2-(substituted)-ethyl]-1-piperazinyl}-1,4-dihydroquinoline-3-carboxylic acid derivatives were synthesized by reacting 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4- dihydroquinoline-3-carboxylic acid with 2-bromo-4-(substituted) acetophenone in the presence of sodium bicarbonate to obtain 1-cyclopropyl-6-fluoro-7-{4-[2-(4- substitutedphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carbox ylic acids 2a-2d. Compound 2a-2d underwent further reaction with different substituted hydrazide, hydroxylamine hydrochloride or methoxylamine in glacial acetic acid to give 3a-7d. In vitro antibacterial activity of the synthesized compounds 3a-7d was studied and the MIC value was determined by the broth dilution method. RESULT: Among all the synthesized compounds 3a-7d some compounds showed antimicrobial activity in comparison to the reference standard ciprofloxacin. CONCLUSION: The compound 6d showed the reasonable good antibacterial activity among all the tested compounds. To understand antibacterial data on structural basis and the interaction of binding sites with bacterial protein receptor, the docking studies were carried out using topoisomerase II DNA gyrase enzymes (PDB ID. 2XCT) by shrodinger's maestro program.

Low dietary n-6/n-3 polyunsaturated fatty acid ratio prevents induced oral carcinoma in a hamster pouch model.[Pubmed:28292553]

Prostaglandins Leukot Essent Fatty Acids. 2018 Sep;136:67-75.

Dietary fatty acid patterns have been linked to the prevalence of certain cancers, however in oral carcinoma is limited. Thus, we investigated the chemopreventive effects of various dietary n-6 and n-3 fatty acids in a 9,10-dimethyl-1,2-benz[a]-anthracene (DMBA)- and betel quid extract (BQE) -induced hamster oral cancer model. Thirty 6-week-old adult male hamsters were housed and divided into normal, low, and high dietary n-6 and n-3 fatty acid groups under DMBA + BQE treatment for 16 weeks. The right buccal pouch of all hamsters were evaluated by tumor number, volume, burden and selected inflammatory parameters. The results indicate that the low dietary n-6/n-3 fatty acid group exhibited a significantly lower tumor number, volume, and burden than those of the other groups. Furthermore, this group had significantly lower nuclear factor-kappaB, proliferating cell nuclear antigen, and cyclin D1 expression in the right buccal pouch tissue. In conclusion, the lower dietary n-6/n-3 fatty acid ratio exerted chemopreventive effects in the DMBA- and BQE-induced hamster oral cancer model.

Discovery of 4-((3'R,4'S,5'R)-6''-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2''-oxodispiro[ cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamido)bicyclo[2.2.2]octane -1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.[Pubmed:28339198]

J Med Chem. 2017 Apr 13;60(7):2819-2839.

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (Ki < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment.