Concise Synthesis of Tunicamycin V and Discovery of a Cytostatic DPAGT1 Inhibitor

Abstract

A short total synthesis of tunicamycin V (1), a non-selective phosphotransferase inhibitor, is achieved via a Büchner-Curtius-Schlotterbeck type reaction. Tunicamycin V can be synthesized in 15 chemical steps from D-galactal with 21 % overall yield. The established synthetic scheme is operationally very simple and flexible to introduce building blocks of interest. The inhibitory activity of one of the designed analogues 28 against human dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1) is 12.5 times greater than 1. While tunicamycins are cytotoxic molecules with a low selectivity, the novel analogue 28 displays selective cytostatic activity against breast cancer cell lines including a triple-negative breast cancer.

Tunicamycins from Marine-Derived Streptomyces bacillaris Inhibit MurNAc-Pentapeptide Translocase in Staphylococcus aureus

“…Since MraY is crucial for the survival of bacteria but absent in eukaryotes, it presents an excellent target for the development of novel antibacterial agents [13,17,27]. As MraY is an enzyme that is essential for the growth of S. aureus, deletion mutants could not survive without complementary copies of mraY [28].…”

“…MraY is a promising drug target for developing new antibacterial agents, though it is yet to be utilized as a target for commercial antibiotics [15]. Although tunicamycins have strong antibacterial activities against some Grampositive bacteria-especially S. aureus-these compounds also inhibit dolichyl-phosphate Nacetylglucosamine-phosphotransferase 1 (DPAGT1) and show cytotoxicity in mammalian cells by damaging the membrane, leading to necroptosis [16,17]. While low specificity and cytotoxicity limited the use of tunicamycins as clinical drugs, recent attempts to achieve higher specificity toward DAPGT1 or antibacterial activity while lowering cytotoxicity has shown modified tunicamycins to be potential anticancer and antibacterial agents [17,18].…”