Synthesis, kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

• Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin. (c) 2012 Elsevier Ltd. All rights reserved.

Subject headings

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Kemi -- Teoretisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)

NATURVETENSKAP  -- Kemi -- Fysikalisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Physical Chemistry (hsv//eng)

NATURVETENSKAP  -- Kemi -- Organisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Organic Chemistry (hsv//eng)

Keyword

Resorcylic acid lactones

Kinase inhibitors

Olefination

Lactamization

methoxybenzyl pmb ethers

force-field

secondary alcohols

tyrosine

kinases

in-vitro

inhibitors

phosphorylation

activation

cancer

potent

ss db

1991

journal of the american chemical society

v113

p7277

ss db

1983

journal of organic chemistry

v48

p4155

Resorcylic acid lactones

Kemi

Publication and Content Type

ref (subject category)

art (subject category)