Design and
Synthesis of Cyclolipopeptide Mimics of
Dysoxylactam A and Evaluation of the Reversing Potencies against P‑Glycoprotein-Mediated
Multidrug Resistance
posted on 2024-03-19, 21:04authored byGuan-Zhou Yang, Lei Wang, Kun Gao, Xi Zhu, Li-Guang Lou, Jian-Min Yue
Inspired by the structure of dysoxylactam A (DLA) that
has been
demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance
(MDR) effectively, 61 structurally simplified cyclolipopeptides were
thus designed and synthesized via an effective method, and their reversing
P-gp-mediated MDR potentials were evaluated, which provided a series
of more potent analogues and allowed us to explore their structure–activity
relationship (SAR). Among them, a well-simplified compound, 56, with only two chiral centers that all derived from amino
acids dramatically reversed drug resistance in KBV200 cells at 10
μM in combination with vinorelbine (VNR), paclitaxel (PTX),
and adriamycin (ADR), respectively, which is more promising than DLA.
The mechanism study showed that 56 reversed the MDR of
tumor cells by inhibiting the transport function of P-gp rather than
reducing its expression. Notably, compound 56 effectively
restored the sensitivity of MDR tumors to VNR in vivo at a dosage
without obvious toxicity.