Antioxidants

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It was established in 1993 that activation of VCAM-1 expression on endothelial cells is partly regulated by a redox signal transduction pathway that is sensitive to inhibition by antioxidants. Pyrrolidine dithiocarbamate (PDTC), a known antioxidant, at 50 mM inhibited over 90% of IL-1p-induced VCAM-1 expression in cultured human umbilical vein endothelial cells (HUVEC) [47,48]. These findings led to the search for new compounds with antioxidant properties as inhibitors of VCAM-1 expression.

Probucol (1), a phenolic antioxidant, was once used worldwide as a lipid-lowering agent [49,50]. While probucol had moderate low-density lipoprotein (LDL)-lowering effects compared to statins, it also significantly lowered high-density lipoprotein (HDL) levels, and caused QTc prolongation. These adverse effects may explain the later withdrawal of probucol from most markets. However, the strong and unique antioxidant properties of probucol have been widely recognized in various settings and are believed to contribute to its anti-atherogenic effects [51-55]. Probucol inhibited neointima formation in animal models of artery balloon injury [56,57] and showed beneficial effects for the prevention of restenosis in humans after angioplasty [58-60]. In a clinical trial, probucol reduced carotid artery intima-media thickness in patients with hypercholesterolemia to the same extent as pravastatin and showed significantly lower incidence of cardiac events than the placebo group [61].

2

Probucol is metabolized to spiroquinone 2 [62]. The latter compound and/or its metabolites have been suspected to be responsible for causing QTc prolongation in some patients. Probucol derivatives have been designed with one of its phenol groups substituted to prevent the formation of the potentially harmful spiroquinone (2) and the other phenol group unsubstituted to retain the antioxidant property [63,64]. Some of these derivatives potently inhibited TNF-a-induced expression of VCAM-1 in cultured human endothelial cells, although probucol itself did not show any effect under the same condition. Hyperbolic correlations have been observed between inhibitory potency on VCAM-1 expression and lipophilicity of compounds among these probucol derivatives. Probucol, despite its strong antioxidant property, presumably does not have the right lipophilicity for potency while some of its derivatives do. Probucol was reported to inhibit VCAM-1 expression in vivo [65], but this effect could be indirect (as opposed to a direct effect in an in vitro cell-based assay) since probucol is known to be able to reduce the levels of oxidized LDL, which induces VCAM-1 expression [66].

AGI-1067 (3), a clinical compound derived from this endeavor, exhibited many in vitro properties desirable in a molecule to treat atherosclerosis [67]. It showed similar antioxidant activity as probucol, potently and selectively inhibited VCAM-1 expression (IC50 = 6 mM) over ICAM-1, and also inhibited MCP-1 expression and human aortic smooth muscle cell proliferation. In animal models, AGI-1067 inhibited the progression of atherosclerosis and lowered LDL levels with neutral or elevating effects on HDL levels [68]. AGI-1067 was not metabolized to probucol in animals or humans, so it is not a prodrug of probucol. It did not exhibit the same pharmacological profile as probucol in animals or humans. AGI-1067 was well tolerated in a 1-year study in hypercholesterolemic monkeys. It lowered LDL levels by 90% and increased HDL levels by 107% at an oral dose of 150mg/kg. Probucol only had modest LDL-lowering effect and decreased HDL levels in the same study.

Histopathological analysis of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067-treated group and minimal-to-moderate atherosclerosis in the vehicle and probucol groups [68]. In clinical trials, AGI-1067 improved lumen dimensions of reference segments of coronary arteries after angioplasty, suggesting a direct positive effect on atherosclerosis; furthermore, AGI-1067 did not cause QTc prolongation [69,70]. The current phase III studies with AGI-1067 will determine the merit of this novel, multifunctional drug in patients with coronary artery disease.

BO-653 (4), another phenolic antioxidant, is worth noting although there have been no reports on its inhibition of VCAM-1 expression. It was derived as a hybrid of probucol and vitamin E with the intention to retain their advantages and overcome their shortcomings as antioxidants [71-73]. Several key pharmacophores were incorporated in the design of BO-653: the phenol group present in both probucol and vitamin E as the antioxidant source; the di-tert-butyl groups from probucol to retain lipophilicity; and the 2,3-dihydrobenzofuran unit derived from a vitamin E analog, which had been known to have increased antioxidant activity compared to

Although it showed weaker reactivity in quenching peroxyl radicals than vitamin E, BO-653 exhibited antioxidant property superior to that of vitamin E against lipid peroxidation [75-77]. In a study on the antioxidant activities of BO-653 against oxidative modification of human LDL particles, BO-653 was consumed faster than vitamin E and retarded consumption of vitamin E. Vitamin E was not consumed until most of the BO-653 was consumed. The formation of lipid hydroperoxides was effectively inhibited until almost all BO-653 was consumed. The superior antioxi-dant potency of BO-653 over vitamin E is likely due to the increased lipophilicity of the molecule and enhanced stability of its radical [77]. BO-653 has shown efficacy in animal models of atherosclerosis and restenosis; in some species the effects were superior to those of probucol. Also, it did not lower HDL levels in animals [78]. BO-653 was reported to be in clinical trials for the treatment of atherosclerosis. Data from these trials will help determine if its advantageous antioxidant property, lipophilicity, and anti-atherosclerotic effects provide superiority over probucol or vitamin E.

HUN-7293 (5) is a cyclic depsipeptide originally isolated from a fungus [46,79]. It is the most potent inhibitor of VCAM-1 expression reported to date, with an IC50 value of 2nM for inhibiting TNF-a-induced expression of VCAM-1 in human endothelial cells [80]. HUN-7293 showed efficacy in animal models of inflammation involving eosinophil infiltration and hypersensitivity reactions, indicating its potential for treating allergic asthma [81]. Compound 6, also fungal-derived, showed similar potency as HUN-7293 to inhibit VCAM-1 expression, indicating that the cyano residue in HUN-7293 is not essential for inhibiting VCAM-1 expression [46].

Various derivatives and analogs of HUN-7293 have been synthesized to understand its structure-activity relationship (SAR) and to discover new, more potent inhibitors of VCAM-1 expression [46,82-85]. Several derivatives and analogs showed comparable potency to HUN-7293, but none have been identified which exhibited significantly better potency. For example, substitution of the ester function in the backbone of HUN-7293 with an amide bond yielded aza-HUN-7239, which had a 20-fold lower potency than HUN-7239 [85]. Compounds 7 and 8, each replacing the cyano residue of HUN-7293 with a different group, showed similar potency as HUN-7293 for inhibition of VCAM-1 expression. Both compounds also inhibited the expression of vascular endothelial growth factor (VEGF) and significantly decreased retinal neovascularization and capillary non-perfusion in a murine model of ischemic retinopathy [46].

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