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. 2022 Aug 1;61(31):e202203225.
doi: 10.1002/anie.202203225. Epub 2022 Jun 10.

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

Katsuhiko Mitachi  1 , David Mingle  1 , Wendy Effah  2 , Antonio Sánchez-Ruiz  3 , Kirk E Hevener  1 , Ramesh Narayanan  2 , William M Clemons Jr  4 , Francisco Sarabia  5 , Michio Kurosu  1
Affiliations

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

Katsuhiko Mitachi et al. Angew Chem Int Ed Engl. .

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.

Keywords: Antimigration Effect; Cytostatic Activity; DPAGT1 Inhibitors; Total Synthesis; Tunicamycins.

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Figures

Figure 1.
Figure 1.
A proposed high-yielding chemical synthesis of tunicamycin V from D-galactal - Retrosynthetic analysis. BFPM: (4,4’-bisfluorophenyl)methoxymethyl, DNs: 2,4-dinitrobenzenesulfonyl
Figure 2.
Figure 2.
Conformational analysis of the aldehyde 10 and rationale of BCS reaction with 9.
Figure 3.
Figure 3.
Growth and migration inhibition of a triple-negative breast cancer MDA-MB-231 by TN-TMPA (28). [a] All assay protocols are summarized in SI. Purple (a1–6): DNA stained with DRAQ5 (CY5 filter: Ex: 635/18, Em: 692/40), Green (a1, a3, a4, and a6): mitochondria stained with NAO (GFP filter: NAO Ex: 482/25, Em: 524/24), Green (a2 and a5): plasma membrane and mitochondria stained with annexin V-FITC (GFP filter: NAO Ex: 482/25, Em: 524/24). [b] Cell migration assays using the Boyden Chamber. Data represent the mean ±SD (p < 0.01).
Scheme 1.
Scheme 1.
A model Büchner-Curtius-Schlotterbeck (BCS) reaction towards tunicamycins. PMB: p-methoxybenzyl, Phth: phthaloyl
Scheme 2.
Scheme 2.
Synthesis of the core structure 21 for tunicamycins.
Scheme 3.
Scheme 3.
Synthesis of tunicamycin V (TN-V, 1), its 5’S-diastereomer (TN-5’S, 26), a water-soluble hydrophobic mimetic analogue (TN-TMPA, 28). NMM: N-Methylmorpholine, EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, NHS: N-hydroxysuccinimide
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