Ascotricins A and B were isolated as novel sphingosine-1-phosphate receptor 1 (S1P(1)) antagonists from a cultured broth of a fungus identified as Ascotricha chartarum Berk. SANK 14186. The two compounds were purified by solvent extraction, reversed-phase (RP) column chromatography and a preparative RP-HPLC. The structures were determined by various NMR experiments and by LC/MS and GC/MS analyses. The S1P(1) antagonist activities were measured by a cyclic AMP assay using S1P(1)-expressing cells and the IC(50) values were 8.2 and 1.8 microM, respectively. In a [(33)P]sphingosine-1-phosphate/S1P(1)-binding assay, those values were 120 and 39 microM, and in a migration assay using human umbilical vein endothelial cells (HUVECs), they were 94 and 28 microM, respectively. Thus, ascotricins A and B are novel S1P(1) antagonists showing an inhibition activity toward HUVEC migration.

01 Jun 1995·Biochemical PharmacologyQ2 · MEDICINE

Effects of KS-501, KS-502 and their enantiomers on calmodulin-sensitive enzyme activity and cellular proliferation

Q2 · MEDICINE

Article

Author: William N. Hait ; Joan Gesmonde ; Elaine Cheng

Calmodulin plays an important role in cellular proliferation as part of a signal transduction pathway activated by phospholipase C. Drugs that block the ability of calmodulin to bind to and activate its target enzymes inhibit the growth of a wide variety of malignant cells. To identify more potent and selective inhibitors of this potential target for new drug development, we studied two recently synthesized compounds, KS-501 and KS-502, for their activity against calmodulin-sensitive enzymes and for their ability to block the growth of parental and multidrug-resistant leukemic cells. KS-501 and KS-502 inhibited the activation of a calmodulin-sensitive cyclic nucleotide phosphodiesterase. The mechanism of enzyme inhibition was through interfering with calmodulin activation rather than through a direct effect on the enzyme. KS-501 was more potent than KS-502 and was studied in greater detail. This compound inhibited the activation of calmodulin kinase I and II, but had less effect against cyclic adenosine 3',5'-monophosphate (cyclic AMP)-sensitive kinase. KS-501 was also more effective than KS-502 in inhibiting the growth of sensitive L1210 leukemic lymphocytes. Both compounds were less effective inhibitors of multidrug-resistant L1210 leukemia than of the parental line. These studies identify a new class of calmodulin inhibitor, with selectivity for calmodulin-dependent kinases over cyclic AMP-dependent protein kinase. Since the total synthesis of the KS-compounds has been accomplished, it should now be possible to develop derivatives with greater activity and selectivity.

01 Jan 1992·Journal of the American Chemical Society

Total syntheses of KS-501, KS-502, and their enantiomers

Author: Dushin, Russell G. ; Danishefsky, Samuel J.

The total syntheses of the title compounds are described.The key step involves the coupling of the anhydrofuranose I (as well as its enantiomer) with salicylate derivative II under the influence of K₂CO₃.Both the epoxidation of anhydrohexenofuranose and the glycosylation of II appear to be stereoselective.

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Indication	Highest Phase	Country/Location	Organization	Date
Thromboembolism	Discovery	Japan	Kyowa Hakko Kogyo Co., Ltd.	-

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