Sarala Balachandran

Synthesis and evaluation of pyrazolo[3,4-b]pyridines and its structural analogues as TNF-α and IL-6 inhibitors

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde/2-formyl-3,4,6-tri-O-methyl-D-glucal/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-alpha and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60-65% inhibition at 10 microM concentration. Amongst these, 51, 52 and 56 showed potent IL-6 inhibitory activity with IC(50)s of 0.2, 0.3 and 0.16 microM, respectively. Compound 56 was not cytotoxic in CCK-8 cells up to the concentration of >100 microM.

Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists

In this letter, we report discovery of diacylphloroglucinol compounds as a new class of GPR40 (FFAR1) agonists. Several diacylphloroglucinols with varying length of acyl functionality and substitution on aromatic hydroxyls were synthesized and evaluated for GPR40 agonism using functional calcium-flux assay. Out of 17 compounds evaluated, 14, 17, 19 and 25 exhibited good GPR40 agonistic activity with EC(50) values ranging from 0.07 to 8 microM (pEC(50) 7.12-5.09), respectively, with maximal agonistic response of 84-102%.

Pharmacology of a novel, orally active PDE4 inhibitor.

Background: Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting. Methods: We evaluated NIS-62949 in a wide range of in vitro and ex vivo cell-based assays to ascertain its anti-inflammatory potential. The compound was evaluated in murine models of lipopolysaccharide-induced endotoxemia and pulmonary neutrophilia. Parameters of airway inflammation, airway hyperreactivity and bronchoconstriction were evaluated in a guinea pig model of antigen-induced allergy. In order to assess the emetic potential, the compound was evaluated biochemically for binding to high-affinity rolipram-binding site. Subsequently, the compound was tested in a surrogate model for emesis, and the results obtained were correlated directly to tests conducted in a Beagle dog model. Results: NIS-62949 is a potent, highly selective PDE4 inhibitor. The compound demonstrated potent ability to inhibit tumor necrosis factor-α release from human peripheral blood mononuclear cells, lymphocyte proliferation and cytokine production. The in vitro profile of NIS-62949 prompted further evaluation of the compound in vivo and the compound was found to be comparable to roflumilast in several experimental models of pulmonary inflammation. Importantly, NIS-62949 displayed a safer profile compared to roflumilast. Conclusions: Our results report the development of a promising, novel PDE4 inhibitor, NIS-62949, with a wider therapeutic window as compared to second-generation PDE4 inhibitors such as roflumilast.

Novel derivatives of ISO-1 as potent inhibitors of MIF biological function.

A series of novel 1,2,4-oxadiazole, phthalimide, amide and other derivatives of ISO-1 were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds inhibited MIF enzymatic activity at levels better than ISO-1. Of note, compounds 7, 22, 23, 24, 25 and 27 inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells and, more importantly, inhibited the MIF-induced production of interleukin-6 (IL-6) and/or interleukin-1beta (IL-1beta) significantly better than ISO-1.

Synthesis and biological activity of novel MIF antagonists

Two series of novel furan and indole compounds were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds from both series inhibited the enzymatic activity of MIF at levels equal to or significantly better than ISO-1 (an early MIF inhibitor). The majority of the compounds that robustly inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells were from the furan series (compounds 5, 9, 13, 15, and 16). In contrast, compounds that markedly inhibited the MIF-induced production of pro-inflammatory cytokines were predominantly from the indole series (compounds 26, 29, and 32).

Acid catalyzed rearrangement and acyl migration studies on 9-dihydro-13-acetylbaccatin-III, a major taxane from Taxus canadensis

Abstract A detailed investigation of the rearrangement of the major taxane from Taxus canadensis enables to suggest the sequence of the reactions involved: 9-dihydro- 13-acetylbaccatin III → abeo-taxanes with intact oxetane and acyl migration → abeo-taxanes with intact oxetane and deacylation → abeo-taxanes with opening of the oxetane and various acyl migrations including two unusual benzoyl shifts.

Biosynthesis of vitamin B12: mechanistic studies on the transfer of a methyl group from C-11 to C-12 and incorporation of 18O

The transfer of a methyl group from C-11 to C-12 in vitamin B12 biosynthesis is shown, by a crossover experiment involving [1,11,17-(CD3)3]-labelled precursors, to occur in an intramolecular fashion; it is found that in Pseudomonas denitrificans, unlike Propionibacterium shermanii, no exchange of the ring A acetate oxygen atoms occurs during formation of the corrin ring.

Biosynthesis of porphyrins and related macrocycles. Part 42. Pulse labelling experiments concerning the timing of cobalt insertion during vitamin B12 biosynthesis

Pulse labelling experiments using 60Co2+ and [methyl-13C, 14C]-S-adenosyl-L-methionine have established that in the anaerobic organism Propionibacterium shermanii cobalt is inserted into the macrocycle after the second and before the fourth C-methylation step.

Biosynthesis of porphyrins and related macrocycles. Part 41. Fate of oxygen atoms as precorrin-2 carrying eight labelled carboxyl groups (13C18O2H) is enzymatically converted into cobyrinic acid

5-Amino[1,4-13C2]laevulinic acid and 5-amino[1-13C]laevulinic acid are synthesised and all three 16O atoms of the latter are exchanged for 18O. The 13C,18O-labelled material is then converted in vitro into precorrin-2 2 by the combined action of four genetically overproduced enzymes. The product is isolated in its aromatised form, sirohydrochlorin 10 and 13C-NMR shows that all 8 carboxyl groups of 10 retain both oxygen atoms throughout the biosynthesis. A cell-free enzyme preparation from Propionibacterium shermanii converts the 13C,18O-labelled sirohydrochlorin 10via2 into cobyrinic acid 4, a late precursor of vitamin B12. 13C-NMR proves that 6 carboxyl groups of cobyrinic acid (b–g, inclusive) retain both oxygen atoms whereas the a-carboxyl group undergoes specific loss of one labelled oxygen atom.