Solenopsin

Solenopsin (C₁₇H₃₅N)is an alkaloidal component of fire ant ( Solenopsis invictica) that potently inhibits angiogenesis via the phosphoinositol-3 kinase (PI3-K) signaling pathway^[1], in addition to contributing to the known and often despised toxic effect of fire ant venom. Solenopsin has also been shown to have cytotoxic, hemolytic, necrotic, insecticidal, antibacterial, antifungal, and anti-HIV properties². Originally synthesized in 1998, several groups have designed novel and creative methods of synthesizing enantiopure solenopsin and other alkaloidal components of ant venom. Though the use of ant venom in a remedial sense has often been marginalized to homeopathic therapies, basic science research is just beginning to uncover the therapeutic value of these alkaloids in human pathologies.

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Biological activity

In vitro studies in embryonic zebrafish in the lab of Jack L. Arbiser at Emory University first revealed solenopsin's anti-angiogenic effects. Further studies have shown that solenopsin inhibits the survival protein Akt in an ATP-competitive manner, without affecting upstream activators PI3-K dependent protein kinase 1 (PDK1) or PI3-K itself. While the direct protein target of solenopsin has not yet been identified, current research suggests a target upstream of PI3-K. In addition to these anti-angiogenic effects, solenopsin potently inhibits the neuronal nitric oxide synthase (nNOS) in a manner that appears to be non-competitive with L-arginine. "The nNOS inhibition by solenopsin compares favorably with the inhibitory potency of widely used nNOS inhibitors³."

Synthesis

The total synthesis of solenopsin has been described by several methods⁴. The method proposed by Bowen et al.¹(Figure 1) starts with alkylation of 4-chloropyridine hydrochloride with a 1-bromoundecane pre-formed Grignard reagent, followed by amidation of the pyridinal nitrogen with phenyl chloroformate, to form 4-Chloro-1-(phenoxycarbonyl)-2-n-undecyl-1,2-dihydropyridine. Phenol is the displaced by t-butoxide, and the pyridine is then methylated at the 6 position. The pyridine ring is then reduced to a 1,2,3,4-tetrahydropyridine via catalytic hydrogenation over palladium. Boc is finally removed to yield (+)-Solenopsin A as trans-2-methyl-6-n-undecylpiperidine. The hydrochloride salt is then formed with addition of HCl and concentration of the solution yields pure Solenopsin A HCl as a white solid. A number of analogs have been synthesized using modifications of this procedure, but Solenopsin A has been shown to have the most potent anti-angiogenic effects.

Figure 1

Summarized schematic of the total solenopsin synthesis

References

1. Arbiser JL, Kau T, Konar M, Narra K, Ramchandran R, Summers SA, Vlahos CJ, Ye K, Perry BN, Matter W, Fischl A, Cook J, Silver PA, Bain J, Cohen P, Whitmire D, Furness S, Govindarajan B, Bowen JP.; Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis. Blood. 2007 Jan 15;109(2):560-5. Epub 2006 Sep 21.
2. Howell G, Butler J, Deshazo RD, Farley JM, Liu HL, Nanayakkara NP, Yates A, Yi GB, Rockhold RW. Cardiodepressant and neurologic actions of Solenopsis invicta (imported fire ant) venom alkaloids. Ann Allergy Asthma Immunol. 2005 Mar;94(3):380-6.
3. Yi GB, McClendon D, Desaiah D, Goddard J, Lister A, Moffitt J, Meer RK, deShazo R, Lee KS, Rockhold RW. Fire ant venom alkaloid, isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide synthase. Int J Toxicol. 2003 Mar-Apr;22(2):81-6.
4. Leclercq, S.; Daloze, D.; Braekman, J.-C. Org. Prep. Proced. Int.1996, 28, 499.