Sesha Natarajan

Synthesis of chiral α- substituted β-hydroxy acid derivatives on solid support

Abstract Enantioselective aldol condensation using solid supported chiral auxiliary was used for the synthesis of α-substituted-β-hydroxy acid and ester. The solid phase synthesis proceeded with high degree of enatioselectivity, as is observed in solution chemistry.

Peptide based P21RAS farnesyl transferase inhibitors : systematic modification of the tetrapeptide CA1A2X motif

Abstract A systematic study of CVFM, a CAAX-derived farnesyl transferase inhibitor, was undertaken to determine the structural elements important for intrinsic activity as well as substrate character. Results indicate a narrowly defined profile for nonsubstrate FT inhibition.

MERCAPTOACYL DIPEPTIDES AS DUAL INHIBITORS OF ANGIOTENSIN-CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE PRELIMINARY STRUCTURE-ACTIVITY STUDIES

Abstract Mercaptoacyl dipeptides were prepared as dual-acting ACE/NEP inhibitors. Inhibition of each enzyme may be explained by different binding models. Structure-activity studies determined that, in this series of compounds, the mercaptopropanoyl dipeptide framework leads to increased affinity for NEP but diminished ACE activity in vivo .

Thrombin receptors as drug discovery targets

A G-protein-coupled thrombin receptor has been identified, cloned and shown to be present on platelets, endothelial cells, fibroblasts and vascular smooth muscle cells. α-Thrombin binds to this receptor via thrombins anion-binding exosite and catalyzes exposure of a new NH2-terminus. The new receptor NH2-terminus acts as an agonistic ‘tethered ligand’ that comprises part of the receptor it activates. The first five or more amino acids of the new NH2-terminus (beginning with SFLLR in the human receptor) can directly activate the receptor in the absence of thrombin. Because thrombin receptor activation may participate in thrombosis, inflammation and fibroproliferative disorders, research is being conducted on several strategies that might interfere with the receptor-mediated pathophysiologic actions of thrombin. The structure-activity relationship for thrombin receptor agonist peptides has been studied in detail, and some general requirements for agonist activity have emerged. Although several peptide-based thrombin receptor antagonists have been described, these earliest examples are not very potent and they appear to be partial agonists in cells other than platelets. Despite the limitations of these prototypes, initial studies with such compounds have demonstrated the importance of this thrombin receptor in α-thrombin-mediated activation of platelets and certain other cells and in arterial thrombosis.

Endothelin analogs which distinguish vasoconstrictor and vasodilator ETB receptors

[Pen 1,11, Nle7, Glu9, Ala18]-Sarafotoxin S6b (BMS-184696) and [Pen1,11, Nle7, Glu9, Leu18]-sarafotoxin S6b (BMS-184697) were synthesized with the aim of preparing ETB receptor antagonists. BMS-184696 was a potent ETA antagonist, an extremely potent vasoconstrictor ETB agonist, and a non-competitive vasodilator ETB antagonist with no agonist activity. BMS-184697 was a potent ETA antagonist, a potent vasoconstrictor ETB agonist, and a vasodilator ETB agonist with moderate potency. The ability of BMS-184696 to activate the vasoconstrictor ETB receptor but not the vasodilator ETB receptor, despite having high affinity binding to the vasodilator ETB receptor as evidenced by its antagonist activity, strongly suggests the existence of ETB receptor subtypes.

Structure-activity studies of endothelin leading to novel peptide ETA antagonists

With the goal of producing receptor antagonists, numerous monocyclic and bicyclic endothelin analogs were prepared and tested for vasoconstrictor activity, receptor affinity and functional antagonist activity. Bis-penicillamine endothelin analogs containing Ala or Asn at position 18 were functional antagonists, with Ki values of 20-40 nM but KB values of about 1 microM (e.g., [Pen1,11, Nle7, Ala18]-endothelin-1, Ki = 42 nM, KB = 1.2 microM). While these peptides are antagonists at the ETA receptor, they appear to be at least partial agonists at another receptor subtype.

3,7-Functionalized-10-methyl phenothiazine: A potential turn scaffold in peptidomimetics

Abstract Molecular modeling studies suggest that the phenothiazine nucleus, embedded in a peptide via attachments at the 3- and 7-positions, may be a possible surrogate for the α-carbon backbone of five residue turns in a variety of proteins. The synthesis of the orthogonally-protected Fmoc 3-aminoethyl-7-carboxyethyl-10-methylphenothiazine ( 1 ) is described.