Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl α-GalCer Analogues

Yogesh Kumar Verma; Bonam Srinivasa Reddy; Mithun S Pawar; Debabrata Bhunia; Halmuthur M Sampath Kumar

doi:10.1021/acsmedchemlett.5b00340

Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl α-GalCer Analogues

ACS Med Chem Lett. 2015 Dec 10;7(2):172-6. doi: 10.1021/acsmedchemlett.5b00340. eCollection 2016 Feb 11.

Authors

Yogesh Kumar Verma¹, Bonam Srinivasa Reddy², Mithun S Pawar², Debabrata Bhunia¹, Halmuthur M Sampath Kumar²

Affiliations

¹ Vaccine Immunology Laboratory, Natural Products Chemistry Division, Indian Institute of Chemical Technology , Hyderabad 500007, India.
² Vaccine Immunology Laboratory, Natural Products Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.

Abstract

Replacement of the amide moiety in the structure of α-GalCer with a 1,2,3-triazole linker is known to elicit a response skewed toward Th2 immunity, and glycolipids containing an aromatic ring in the terminus of their acyl or phytosphingosine structural component exhibit an enhanced Th1 immune response. In the current study, synthesis and immunological screening of a focused library of benzyloxyalkyl-substituted 1,2,3-triazolyl α-GalCer analogues are reported. The novel α-GalCer analogues activate invariant natural killer T (iNKT) cells via CD1d mediated presentation, which was confirmed by in vitro tests performed on iNKT hybridomas incubated with CD1d proteins. When tested on isolated murine splenocytes, the T1204B and T1206B compounds stimulated higher levels of both IFN-γ and IL-4 cytokine expression in vitro compared to that of α-GalCer.

Keywords: IFN-γ; IL-4; Th1/Th2; benzyloxyalkyl α-GalCer; iNKT hybridoma; kinetic release.