Y.Krishna Reddy

14,15-Epoxyeicosa-5(Z)-Enoic Acid. A Selective Epoxyeicosatrienoic Acid Antagonist That Inhibits Endothelium-Dependent Hyperpolarization and Relaxation in Coronary Arteries

Endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle are mediated by endothelium-derived hyperpolarizing factors (EDHFs). EDHF candidates include cytochrome P-450 metabolites of arachidonic acid, K+, hydrogen peroxide, or electrical coupling through gap junctions. In bovine coronary arteries, epoxyeicosatrienoic acids (EETs) appear to function as EDHFs. A 14,15-EET analogue, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) was synthesized and identified as an EET-specific antagonist. In bovine coronary arterial rings preconstricted with U46619, 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET induced concentration-related relaxations. Preincubation of the arterial rings with 14,15-EEZE (10 &mgr;mol/L) inhibited the relaxations to 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET but was most effective in inhibiting 14,15-EET–induced relaxations. 14,15-EEZE also inhibited indomethacin-resistant relaxations to methacholine and arachidonic acid and indomethacin-resistant and l-nitroarginine-resistant relaxations to bradykinin. It did not alter relaxation responses to sodium nitroprusside, iloprost, or the K+ channel activators (NS1619 and bimakalim). Additionally, in small bovine coronary arteries pretreated with indomethacin and l-nitroarginine and preconstricted with U46619, 14,15-EEZE (3 &mgr;mol/L) inhibited bradykinin (10 nmol/L)–induced smooth muscle hyperpolarizations and relaxations. In rat renal microsomes, 14,15-EEZE (10 &mgr;mol/L) did not decrease EET synthesis and did not alter 20-hydroxyeicosatetraenoic acid synthesis. This analogue acts as an EET antagonist by inhibiting the following: (1) EET-induced relaxations, (2) the EDHF component of methacholine-induced, bradykinin-induced, and arachidonic acid–induced relaxations, and (3) the smooth muscle hyperpolarization response to bradykinin. Thus, a distinct molecular structure is required for EET activity, and alteration of this structure modifies agonist and antagonist activity. These findings support a role of EETs as EDHFs.

Ag(I)-promoted Suzuki–Miyaura cross-couplings of n-alkylboronic acids

Abstract Ag(I) salts significantly enhance palladium-catalyzed Suzuki–Miyaura cross-couplings of n-alkylboronic acids with a wide variety of aryl and alkenyl halides/triflates.

20-hydroxyeicosatetraenoic acid (20-HETE): structural determinants for renal vasoconstriction.

The effects of natural and synthetic eicosanoids on the diameter of rat interlobular arteries studied in vitro were compared to that of the potent, endogenous vasoconstrictor 20-HETE. Vasoconstrictor activity was optimum for chain lengths of 20-22 carbons with at least one olefin or epoxide between located between C(13)-C(15) and an oxygen substituent at C(20)-C(22). The presence of delta (Zou et al. Am. J. Physiol. 1996, 270, R228; Gebremedhin, D. et al. Am. J. Physiol. 1998, 507, 771)-, delta (Carroll et al. Am. J. Physiol. 1996, 271, R863; Vazquez et al. Life Sci. 1995, 56, 1455)-, or delta (Imig et al. Hypertension 2000, 35, 307; Lopez et al. Amer. J. Physiol. 2001, 281, F420)-olefins had no influence on the vasoconstrictor response whereas the introduction of a C(7)-thiomethylene enhanced potency. A sulfonamide or alcohol, but not a lactone, could replace the C(1)-carboxylate. These data were used to construct a putative binding domain map of the 20-HETE receptor consisting of: (i) a comparatively open, hydrophilic binding site accommodating the C(1)-functionality; (ii) a hydrophobic trough spanning the olefins; (iii) a shallow pocket containing a critical pi-pi binding site in the vicinity of the pi (Ito et al. Am. J. Physiol. 1998, 274, F395; Quigley, R.; Baum, M.; Reddy, K. M.; Griener, J. C.; Falck, J. R. Am. J. Physiol. 2000, 278, F949)-olefin; and (iv) an oxyphilic binding site proximate to the omega-terminus.

Practical, enantiospecific syntheses of 14,15-EET and leukotoxin B (vernolic acid)

Abstract Cytochrome P450BM3 and its F87V mutant were exploited for a convenient, laboratory scale (1 mmol) preparation of 14( S ),15( R )-epoxyeicosatrienoic acid [14( S ),15( R )-EET] from arachidonic acid and (+)-leukotoxin B [(+)-12( S ),13( R )-vernolic acid] from linoleic acid, respectively. Their enantiomers were accessed via a four-step chemical inversion.

Stereospecific synthesis of EET metabolites via Suzuki-Miyaura coupling

Abstract Bioactive, chain-shortened EET metabolites, viz. 8,9-epoxytetradec-5(Z)-enoic acid and 9,10-epoxyoctadec-6(Z),12(Z)-dienoic acid, were prepared via Suzuki–Miyaura cross-couplings of n-alkylboronic acids with chiral vinyl iodides.