Dynamic Function of the Alkyl Spacer of Acetogenins in Their Inhibitory Action with Mitochondrial Complex I (NADH-Ubiquinone Oxidoreductase)

Abstract

Studies on the inhibitory mechanism of acetogenins, the most potent inhibitors of mitochondrial complex I (NADH-ubiquinone oxidoreductase), are useful for elucidating the structural and functional features of the terminal electron transfer step of this enzyme. Previous studies of the structure-activity relationship revealed that except for the alkyl spacer linking the two toxophores (i.e., the hydroxylated THF and the gamma-lactone rings), none of the multiple functional groups of these inhibitors is essential for potent inhibition. To elucidate the function of the alkyl spacer, two sets of systematically selected analogues were synthesized. First, the length of the spacer was varied widely. Second, the local flexibility of the spacer was specifically reduced by introducing multiple bond(s) into different regions of the spacer. The optimal length of the spacer for inhibition was approximately 13 carbon atoms. The decrease in the strength of the inhibitory effect caused by elongating the spacer from 13 carbons was much more drastic than that caused by shortening. Local flexibility in a specific region of the spacer was not important for the inhibition. These observations indicate that the active conformation of the spacer is not an extended form, and is not necessarily restricted to a certain rigid shape. Moreover, an analogue in which a spacer covering 10 carbon atoms was hardened into a rodlike shape still maintained a potent inhibitory effect. Our results strongly suggest that the spacer portion is free from steric congestion arising from the putative binding site probably because there is no cavity-like binding site for the spacer portion. The manner of acetogenin binding to the enzyme may not be explained by a simple "key and keyhole" analogy.

In vitro and in vivo antiproliferative activity of laherradurin and cherimolin‐2 of annona diversifolia saff

“…Studies on the structure-activity relationship of the ACG indicate that the aliphatic chain with 13 carbon atoms of the spacer that unites the THF system and the γ-lactone represents an essential factor in its potent activity (Miyoshi et al, 1998;Takada et al, 2000;Abe et al, 2005). The laherradurin molecule contains the aforementioned length in its chain spacer, laherradurin were: 10× = 0.15 mg/kg/day, 100× = 1.5 mg/ kg/day and 500× = 7.5 mg/kg/day on HeLa, and 100× = 1.5 mg/kg/day and 500× = 7.5 mg/kg/day on SW-480 tumors.…”

Total synthesis of squafosacin F: stereodivergent approach to mono-tetrahydrofuran acetogenins

“…In a previous study of cis-solamin synthesis, 7 tandem cyclization Scheme 2 Synthesis of diepoxyester 7. Reagents and conditions: (a) Ac 2 O, pyridine, r.t., 52%; (b) TBHP, D-(À)-DIPT, Ti(O i Pr) 4 , 4Å molecular sieves, CH 2 Cl 2 , -20 C, 98% (>95% ee); (c) MOMCl, DIPEA, CH 2 Cl 2 , reflux; (d) K 2 CO 3 , MeOH, r.t., 88% (2 steps); (e) TBHP, D-(À)-DIPT, Ti(O i Pr) 4 , 4Å molecular sieves, CH 2 Cl 2 , -20 C, 86%; (f) Dess-Martin periodinane, NaHCO 3 , CH 2 Cl 2 , r.t. then Ph 3 P]CHCO 2 Et, r.t.; (g) H 2 , Rh/Al 2 O 3 , THF, r.t., 80% (2 steps).…”

“…Aer stirring for 40 min, the mixture was added Ph 3 PCHCO 2 Et (4.04 g, 11.6 mmol) at same temperature. Aer stirring for 15 min, the mixture was quenched with saturated aqueous NaHCO 3 solution, diluted with Et 2 O, washed with 10% aqueous Na 2 SO 3 solution, H 2 O and brine, dried over anhydrous MgSO 4 and Na 2 SO 4 , and then concentrated in vacuo to give a crude a,bunsaturated ester which was used for the next step without further purication.…”

“…To a stirred solution of tetrahydrofuran 8 (20.0 mg, 0.0769 mmol) in CH 2 Cl 2 (2.56 mL) were added WSC (88.5 mg, 0.462 mmol), DMAP (2.8 mg. 0.0231 mol), and 3,5-dinitrobenzoic acid (48.9 mg, 0.231 mmol) at room temperature. Aer stirring for 15 min, the mixture was quenched with saturated aqueous NaHCO 3 solution, diluted with Et 2 O, washed with H 2 O, and brine, dried over anhydrous MgSO 4 and Na 2 SO 4 , and then concentrated in vacuo to give a crude dinitrobenzoate which was used for the next step without further purication.…”

“…A chain length of C 13 is important for achieving the most potent inhibitory activity. 4 cis-Solamin is a particularly active mono-tetrahydrofuran acetogenin. 5 It was isolated from a root extract of Annona muricata L. and its structure was determined by Cavé et al in 1998. It has a C13 spacer and therefore shows strong mitochondrial complex I inhibitory activity.…”