Open AccessTotal Synthesis and Biological Evaluation of Clavatadines C–E
Author(s) -
Kylee Maxfield,
Morgan Payne,
Stephen Chamberland
Publication year - 2022
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.2c02913
Subject(s) - total synthesis , stereochemistry , cytotoxicity , amide , natural product , tyrosine , chemistry , protecting group , diamine , cell culture , cancer cell lines , biology , cancer research , biochemistry , cancer , cancer cell , genetics , organic chemistry , alkyl , in vitro
We described herein the application of a convergent and protecting-group avoidant approach that led to the first total synthesis of the marine natural products clavatadine D ( 4 ) and E ( 5 ), and the second total synthesis of clavatadine C ( 3 ). In each case, a key amide-coupling afforded an immediate precursor of each natural product in a rapid manner from structurally similar western and eastern portions that derived from an ester of l-tyrosine and butane-1,4-diamine, respectively. A deprotection step free of detectable byproducts cleanly provided the remaining known members of the clavatadine family of natural products. Each total synthesis required five steps (longest linear sequence) with overall yields of 30-37%, 26-39%, and 28-50% for clavatadine C ( 3 ), D ( 4 ), and E ( 5 ), respectively. A screen of their potential anticancer activity against the NCI-60 cell line panel revealed cytotoxicity levels up to 38% across a broad spectrum of tumor types. Although clavatadine C ( 3 ) was relatively benign, clavatadine D ( 4 ) exhibited 20-38% growth inhibition against a wide array of cancer cell types including leukemia, non-small-cell lung, colon, ovarian, and breast. Clavatadine E ( 5 ) was active against two types of human brain tumors.