Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 86, Issue 2, Pages 1462-1470Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.0c02057
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Funding
- National Natural Science Foundation of China [81760626, 21977021]
- BAGUI Young Scholar Program of Guangxi, Guangxi Funds for Distinguished Experts
- National Research Foundation of Korea (NRF) - Korean Government [NRF-2016M3A9B6903499]
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Nitidumpeptins A and B, two novel cyclic hexapeptides isolated from Zanthoxylum nitidum var. tomentosum, have unique structures and demonstrated synergistic antiproliferative activity in combination with gefitinib against gefitinib-resistant lung cancer cells. The total synthesis of these compounds confirmed their absolute configurations and further studies revealed the mechanism of action involved the suppression of YAP expression in the cancer cells.
Nitidumpeptins A and B (1 and 2), two novel cyclic hexapeptides, were isolated from the herb Zanthoxylum nitidum var. tomentosum. Their planar structures were elucidated based on NMR and MS spectrometric analysis, and the absolute configurations were determined by the Marfey's method. Structurally, 1 is a unique peptide with a backbone bearing a pyrrolidine-2,5-dione unit, which is the first occurrence moiety specifically in a naturally occurring cyclohexapeptide. The total synthesis of 1 and 2 was achieved by solution-phase in parallel with solid-phase peptide synthesis, and their absolute configurations were further confirmed. The combination of 2 with gefitinib exhibited synergistic antiproliferative activity in acquired gefitinib-resistant non-small cell lung cancer cells (HCC827-gef). The underlying mechanism for the antiproliferative activity of 2 was in part associated with the suppression of YAP expression in HCC827-gef cells.
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