Synthesis and Antimicrobial Evaluation of Fire Ant Venom Alkaloid Based 2-Methyl-6-alkyl-Δ1,6-piperideines.

The first synthesis of 2-methyl-6-pentadecyl-Δ1,6-piperideine (1), a major alkaloid of the piperideine chemotype in fire ant venoms, and its analogues, 2-methyl-6-tetradecyl-Δ1,6-piperideine (2) and 2-methyl-6-hexadecyl-Δ1,6-piperideine (3), was achieved by a facile synthetic method starting with glutaric acid (4) and urea (5). Compound 1 showed in vitro antifungal activity against Cryptococcus neoformans and Candida albicans with IC50 values of 6.6 and 12.4 µg/mL, respectively, and antibacterial activity against vancomycin-resistant Enterococcus faecium with an IC50 value of 19.4 µg/mL, while compounds 2 and 3 were less active against these pathogens. All three compounds strongly inhibited the parasites Leishmania donovani promastigotes and Trypanosoma brucei with IC50 values in the range of 5.0-6.7 and 2.7-4.0 µg/mL, respectively.

Stereodivergent access to cis- and trans-3,5-disubstituted 1,4-thiazane 1-oxides by cyclization of homochiral ß-amino sulfoxides and sulfones. The preparation of isomeric ant venom alkaloids.

Intramolecular conjugate additions of homochiral (E)-1-alkenyl 2-aminoalkyl sulfoxides and sulfones were investigated. The relative position of the 3,5-substituents of the resulting 1,4-thiazane oxides was found to be dependent on the oxidation state of the sulfur atom, demonstrating a simple and highly stereodivergent synthetic protocol. Selected cis- and trans-3,5-disubstituted 1,4-thiazane dioxides were converted to cis- and trans-2,5-disubstituted pyrrolidines, known ant venom alkaloids.

Efficient synthesis of α,ß-unsaturated alkylimines performed with allyl cations and azides: application to the synthesis of an ant venom alkaloid.

An efficient synthesis of α,ß-unsaturated alkylimines at low temperature using azides has been developed. Carbocations generated from allyl alcohols helped achieve a rapid conversion under mild conditions with azides to afford reactive α,ß-unsaturated imines. Hydroxy or alkoxy groups are essential for these transformations, and utilizing readily accessible allyl alcohols gave a wide extension of substrates. The efficiency of this novel method is demonstrated in the total synthesis of an iminium ant venom alkaloid.

Metal-catalyzed coupling reactions on an olefin template: the total synthesis of (13E,15E,18Z,20Z)-1-hydroxypentacosa- 13,15,18,20-tetraen-11-yn-4-one 1-acetate.

The naturally occurring ant venom (13E,15E,18Z,20Z)-1-hydroxypentacosa-13,15,18,20-tetraen-11-yn-4-one 1-acetate was synthesized stereospecifically using a series of metal-mediated cross-coupling reactions. The use of the difunctional olefin template (E)-1-chloro-2-iodoethylene as the central, pseudosymmetrical building block facilitated a fully convergent and, thus, efficient strategy to prepare this polyunsaturated natural product.

RAST-inhibition studies of the imported fire ant Solenopsis invicta with whole body extracts and venom preparations.

Whole body extracts of imported fire ants (IFAWBE) are the only reagents currently available for diagnosis and immunotherapy of patients with anaphylaxis to these Hymenoptera. To characterize better IFAWBE of the species Solenopsis invicta, we evaluated the sera of 29 patients with systemic or large local reactions to imported fire ant (IFA) stings. Forty-eight percent (14/29) of these sting-sensitive patients were IFAWBE RAST positive (greater than or equal to 6% binding of total radioactivity added). With a pool of sera with an initial IFAWBE-RAST value of 16.2% binding, we evaluated RAST inhibition by IFA venom (IFAV), IFAWBE, and the venom component, transpiperidine. Maximum RAST inhibition obtained was 84% with 300 micrograms/ml of IFAV, 95% with 5 mg/ml of protein IFAWBE, and insignificant with undiluted transpiperdine. We conclude that IFAWBE contains large quantities of immunoreactive venom components other than transpiperidine and that the allergenicity of IFAWBE and venom resides in the small amount of protein present in IFAV.