SANT-2

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SANT-2
Identifiers
  • N-[3-(1H-benzimidazol-2-yl)-4-chlorophenyl]-3,4,5-triethoxybenzamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H26ClN3O4
Molar mass479.96 g·mol−1
3D model (JSmol)
  • CCOC1=CC(=CC(=C1OCC)OCC)C(=O)NC2=CC(=C(C=C2)Cl)C3=NC4=CC=CC=C4N3
  • InChI=1S/C26H26ClN3O4/c1-4-32-22-13-16(14-23(33-5-2)24(22)34-6-3)26(31)28-17-11-12-19(27)18(15-17)25-29-20-9-7-8-10-21(20)30-25/h7-15H,4-6H2,1-3H3,(H,28,31)(H,29,30)
  • Key:VQOJFGFKIVFMDH-UHFFFAOYSA-N

SANT-2 is a small-molecule antagonist of the sonic hedgehog (Shh) pathway,[1] a developmental signaling cascade implicated in tissue patterning, stem cell maintenance, and the progression of various cancers. By targeting the smoothened (SMO) receptor, SANT-2 disrupts aberrant Shh pathway activation, thereby inhibiting downstream transcriptional programs that drive uncontrolled cell proliferation and survival.[1] Due to its potency and specificity, SANT-2 has become a tool for studying Hedgehog-dependent oncogenesis and holds potential as a lead compound for the development of targeted anticancer therapeutics.

Pharmacology

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SANT-2 is a potent antagonist of the Smoothened (SMO) receptor, a key component of the Sonic hedgehog (Shh) signaling pathway, displaying a dissociation constant (KD) of 12 nM for SMO binding. Its pharmacological profile is characterized by strong allosteric binding—similar to the first-in-class SMO antagonist SANT-1, interfering with the receptor’s activity even in the presence of endogenous and synthetic agonists. SANT-2 efficiently displaces radiolabeled SAG-1.3 and cyclopamine bound to SMO, with inhibition constants (Kd) of 7.8 nM and 8.4 nM, respectively, highlighting its high affinity and specificity for this receptor.[1][2][3]

Synthesis

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SANT-2 is synthesized by coupling 2-chloro-5-nitrobenzoic acid with o-phenylenediamine to form a benzimidazole intermediate. Béchamp reduction of the nitro group affords the corresponding aniline, which is then coupled with 3,4,5-triethoxybenzoic acid via amide formation to yield SANT-2.[1]

References

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  1. ^ a b c d Büttner A, Seifert K, Cottin T, Sarli V, Tzagkaroulaki L, Scholz S, et al. (July 2009). "Synthesis and biological evaluation of SANT-2 and analogues as inhibitors of the hedgehog signaling pathway". Bioorganic & Medicinal Chemistry. 17 (14): 4943–4954. doi:10.1016/j.bmc.2009.06.008. PMID 19541490.
  2. ^ Rominger CM, Bee WL, Copeland RA, Davenport EA, Gilmartin A, Gontarek R, et al. (June 2009). "Evidence for allosteric interactions of antagonist binding to the smoothened receptor". The Journal of Pharmacology and Experimental Therapeutics. 329 (3): 995–1005. doi:10.1124/jpet.109.152090. PMID 19304771.
  3. ^ Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (October 2002). "Small molecule modulation of Smoothened activity". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14071–14076. Bibcode:2002PNAS...9914071C. doi:10.1073/pnas.182542899. PMC 137838. PMID 12391318.