Isolation and Structural Modification of 7-Deoxynarciclasine and 7-Deoxy-trans-Dihydronarciclasine^,1

Abstract

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI50 0.1 to <0.01 microg/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.

Antineoplastic Agents. 454. Synthesis of the Strong Cancer Cell Growth Inhibitors trans-Dihydronarciclasine and 7-Deoxy-trans-dihydronarciclasine

“…Hydrogenation afforded as the major product the expected cis -dihydronarciclasine ( 3a ) accompanied by the trans isomer ( 1a ) and iso -narciclasine ( 4a ). Subsequently, trans -dihydronarciclasine ( 1a ) was found to exhibit strong cancer cell growth inhibition (mean panel GI 50 12.6 nM) against the U.S. National Cancer Institute (NCI) panel of cancer cell lines3a,b whereas its cis isomer ( 3a )3c was only very weakly active (mean panel GI 50 3800 nM). Importantly, the trans isomer ( 1a ) gave an active Compare correlation coefficient of 0.92 in respect to (+)-pancratistatin (5) 3a.…”

“…Subsequently, trans -dihydronarciclasine ( 1a ) was found to exhibit strong cancer cell growth inhibition (mean panel GI 50 12.6 nM) against the U.S. National Cancer Institute (NCI) panel of cancer cell lines3a,b whereas its cis isomer ( 3a )3c was only very weakly active (mean panel GI 50 3800 nM). Importantly, the trans isomer ( 1a ) gave an active Compare correlation coefficient of 0.92 in respect to (+)-pancratistatin (5) 3a. The trans isomer ( 1a ) also showed strong activity against a range of RNA viruses while the synthetic cis isomer ( 3a ) was completely inactive 4…”

Synthesis and evaluation of C-ring aromatized analogues of phenanthridone alkaloids

“…Among these, the most intriguing biological property is the profound cancer cell growth inhibitory activity. Although the reported in vitro potencies vary, many of this class of alkaloids were found to have GI 50 values in the low nM concentration range (Pettit et al, 2005(Pettit et al, , 2006. Thus, natural phenanthridone alkaloids and their derivatives have been under preclinical development for nearly two decades.…”

Synthesis of Structurally Simplified Analogues of Pancratistatin: Truncation of the Cyclitol Ring

“…To date, 7-deoxy- trans -dihydronarciclasine ( 4 ), possessing three hydroxyl groups in ring C, represents the only ring C dehydroxylated analog with significant levels of activity 11b,15. Therefore, we wondered whether structural simplification of pancratistatin could be achieved not by removing hydroxyl functionality, as was attempted with the above-mentioned efforts, but by modification of the carbon skeleton of the ring C while still preserving at least three hydroxyl groups.…”