Unexpected stereochemical tolerance for the biological activity of tyroscherin

Abstract

Here we describe the concise syntheses of the 15 diastereomers and key analogs of the natural product tyroscherin. While systematic analysis of the analogs clearly demonstrated that the hydrocarbon tail is important for biological activity, structure-activity relationship studies of the complete tyroscherin diastereoarray revealed a surprisingly expansive stereochemical tolerance for the cytotoxic activity. Our results represent a departure from the tenet that biological activity is constrained to a narrow pharmacophore, and highlight the recently emerging appreciation for stereochemical flexibility in defining the essential structural elements of biologically active small molecules.

Biakamides A–D, Unique Polyketides from a Marine Sponge, Act as Selective Growth Inhibitors of Tumor Cells Adapted to Nutrient Starvation

“…Removal of the solvent from AcOEt extract under reduced pressure gave a crude product which was purified by SiO 2 column (hexane:AcOEt = 5:1 to 1:1) to give 6 (636 mg, 50%) as a colorless oil. The spectroscopic and physical data were identical to those reported …”

“…Using the same procedures as those for the synthesis of the (4 R ,6 S )-isomer, (4 S ,6 R )-biakamide A was obtained starting from (2 S ,4 S )-5-(( tert -butyldiphenylsilyl)­oxy)-2,4-dimethylpentan-1-ol …”

“…The spectroscopic and physical data were identical to those reported. 41 Methyl (4R,6R,E)-7-((tert-Butyldiphenylsilyl)oxy)-4,6-dimethylhept-2-enoate (7). Iodobenzene diacetate (1.22 g, 2.8 mmol, 2.3 equiv) and TEMPO (25.6 mg, 0.17 mmol, 0.1 equiv) were added to a solution of 7 (607 mg, 1.6 mmol) in CH 2 Cl 2 (20 mL), and the whole mixture was stirred for 3 h at rt.…”

Synthesis and Biological Activities of Tyroscherin Analogs

“…6 1901 sensitive retaining biological activity. The great tolerance of the stereochemistry of the side chain of tyroscherin in an earlier report 5 and the insignificant difference in activity due to the substituents of the phenyl ring tell us that the essential structural element for the biological activity of tyroscherin is still undisclosed.…”

“…5 What they found was a stereochemical tolerance for cytotoxic activity, which is quite unusual in most cases with spacially well-defined narrow phamacophores. They also tested one analog without a hydroxyl group in the phenyl ring of tyroscherin.…”