A Highly Convergent Synthesis of Myristoyl-carba(dethia)-coenzyme A

• Published in: European Journal of Organic Chemistry Vol. 2010; no. 9; pp. 1728 - 1735
• Main Authors: Tautz, Lutz, Rétey, Janos
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-03-2010; WILEY‐VCH Verlag; Wiley-VCH
• Subjects: Antifungal agents; Antiviral agents; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Carbohydrates. Nucleosides and nucleotides; Chemistry; Coenzyme A; Exact sciences and technology; Fundamental and applied biological sciences. Psychology; Inhibitors; Methods. Procedures. Technologies; N-Myristoylation; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Antineoplastic agent; Epilepsy; Anticonvulsant; Glycine; Phosphorus Organic compounds; Antifungal agent; Antiviral; Cleavage; Coenzyme A; Membrane; Nucleoside; Chemical synthesis; Human; Antiviral agents; Adenosine; Catalytic reaction; Enzyme; Antifungal agents; Retroviridae; Enzyme inhibitor; Malignant tumor; N-Myristoylation; Lentivirus; Ketone; Protein; Virus; Infection; In vivo; Enzymatic method; α-Aminoacid; Inhibitors; Aminoacid; Analog; Nucleotide; Organic phosphate; Human immunodeficiency virus; Cancer; Pantothenic acid
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200901410

Co‐translational myristoylation of the N‐terminal glycine residues of diverse signalling proteins is required for membrane attachment and proper function of these molecules. The transfer of myristate from myristoyl‐coenzyme A (myr‐CoA) is catalysed by the enzyme N‐myristoyltransferase (Nmt). Nmt has been implicated in a number of human diseases, including cancer and epilepsy, as well as in pathogenic mechanisms such as fungal and virus infections, including HIV and hepatitis B. Rational design has led to the development of potent competitive inhibitors, including several non‐hydrolysable acyl‐CoA substrate analogues. Linear synthetic strategies, following the route of the original CoA synthesis, however, generate such analogues in very low overall yields that typically are not sufficient for in vivo studies. Herewe present a new, highly convergent synthesis of myristoyl‐carba(dethia)‐coenzyme A (1) that allows this substrate analogue to be obtained in a yield 11 times higher than that of the reported linear synthesis. In addition, enzymatic cleavage of the adenosine‐2′,3′‐cyclophosphate in the last step of the synthesis proved to be an efficient way to obtain the isomerically pure 3′‐phosphate 1 free of the 2′‐phosphate 13.
A highly convergent synthesis of myristoyl‐carba(dethia)‐coenzyme A (1) is presented. Compound 1 is a non‐hydrolysable substrate analogue and potent inhibitor of N‐myristoyltransferase (Nmt), a potential drug target for anticancer, antiepilepsy, antifungal and antiviral agents.