Natural product

Total Synthesis of Natural Products

Total synthesis of complex natural products remains among the most exciting and dynamic areas of chemical research. From an applied standpoint, having sustainable and reliable access to biologically active natural isolates can demystify new areas of biology or provide promising candidates for drug discovery and thus, the field is moving toward simplifying the way molecules can be made. Our group performed natural product synthesis not only for structural investigation/confirmation/correction, but also as a test for novel synthetic transformations and classical functional group inter conversions. We are in effort to conduct total syntheses of following natural products and also discovery of enhanced bio-active compounds by structure-activity relationship (SAR) studies.

 

   Our recent accomplishments include:

Structural Revision of Baulamycin A and Structure-Activity Relationships of Baulamycin A Derivatives

  (J. Org. Chem. 2017. 15;82(24):12947-12966.)

  • Baulamycin A serves as a novel inhibitor of SbnE and AsbA and it provides a promising starting point for designing substances that are effective against drug-resistant pathogens such as methicillin-resistant S. aureus (MRSA) and B. anthracis. We accomplished structural revision by synthesizing and NMR analysis of two different isomeric baulamycin A along with the proposed structure. Extensive SAR study was performed using natural product derivatives, which provides useful insight into the design of novel SbnE inhibitors. Key features of the convergent and fully stereocontrolled route include Evans Aldol, Brown allylation, prolinol amide-derived alkylation/desymmetrization, and Carreira alkynylation reaction.

 

Reprinted with permission from (J. Org. Chem. 2017, 15, 82, 12947-12966). Copyright (2017) American Chemical Society.

 

 Lucentamycin A

  • Lucentamycin A, naturally occurring tripeptide found to have significant in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 0.20 µM. Synthesis of the E-isomer of the proposed structure was performed in an attempt to define the correct stereochemistry of this natural product. The synthetic route developed employs a stereoselective Rh-catalyzed reductive cyclization process to generate the key pyrrolidine residue in the target and a stereospecific inversion of the Z-olefin geometry to form desired E-isomer.

 

 

   Militarinone D

  • Militarinone D induces and enhances neurite sprouting in PC12 cells at a concentration of 20 μM and shows significantly induce neurite outgrowth in the absence of Nerve Growth Factor (NGF). We developed a straight forward route which includes key reactions like enzymatic desymmetrization, cis/trans isomerization, Horner–Wardsworth–Emmons olefination, and addition of an organolithium species to a highly conjugated chiral aldehyde.

 

 

   Mupirocin H

  • Mupirocin, a naturally occurring polyketide metabolite, shows activity against gram-positive bacteria, including methicillin-resistant S. aureus (MRSA) and clinically used for the treatment of bacterial skin infections. We have developed two different routes for this natural product synthesis by using key reactions like crotyl boration, Grubbs cross metathesis, cobalt mediated Reformatsky reaction, Still-Gennari olefination, Pd-catalysed stereoselective cis epoxide substitution reaction. Furthermore, our synthetic compound inhibits SbnE enzyme, a synthetase required for staphyloferrin B biosynthesis.

 

 

   Natural Products Synthesized from Chiral Aziridines

  • Militarinone D induces and enhances neurite sprouting in PC12 cells at a concentration of 20 μM and shows significantly induce neurite outgrowth in the absence of Nerve Growth Factor (NGF). We developed a straight forward route which includes key reactions like enzymatic desymmetrization, cis/trans isomerization, Horner–Wardsworth–Emmons olefination, and addition of an organolithium species to a highly conjugated chiral aldehyde.

 

Natural Product-Inspired Drug Discovery

Natural Products have been important sources of useful drugs from prehistoric times to the present. Total synthesis of natural products with interesting biological activities is paving the way for the preparation of new and improved analogues.

 

   Our recent publications contain:

 Identification of the First Selective Activin Receptor-Like Kinase 1 Inhibitor

  (J. Med. Chem. 2017. 23;60(4):1495-1508.)

  • We successfully explored the structure-based design of several bioactive derivatives of L-783277 and found saturated analogs of L-783277, as selective (6/342 kinase) and potent (more potent than L-783277) ALK1 Inhibitor. Bioactive saturated derivative of L783277 promoted angiogenesis in both endothelial tube formation and microfluidic chip based 3D angiogenesis assays, suggesting that it could be a lead compound for therapeutic angiogenesis agents.

 

Reprinted with permission from (J. Med. Chem. 2017, 23, 60, 1495-1508). Copyright (2017) American Chemical Society.

 

 Identification of a unique L-783277 derivative that targets both lymphangiogenesis and angiogenesis

  (J. Med. Chem​. 2019. 24;62(20):9141-9160.)

  • VEGFR3 and VEGFR2 have been identified as effective targets for the suppression of tumor lymphangiogenesis and angiogenesis. There are no currently available highly selective VEGFR3 and VEGFR2 inhibitors.

  •  By incorporating rigidifying ring into the 14-membered chiral resorcylic acid lactone system, kinase selectivity was greatly enhanced against VEGFR3, VEGFR2, FLT3 (17) compared than L-783277.

  • 17 effectively suppresses both lymphangiogenesis and angiogenesis.

Reprinted with permission from (J. Med. Chem. 2019, 24, 62, 9141-9160). Copyright (2019) American Chemical Society.

 

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