Synthesis and Biological Evaluation of Aromatic Analogues of Conduritol F,l-chiro-Inositol, and Dihydroconduritol F Structurally Related to the Amaryllidaceae Anticancer Constituents

Abstract

Pancratistatin is a potent anticancer natural product, whose clinical evaluation is hampered by the limited natural abundance and the stereochemically complex structure undermining practical chemical preparation. Fifteen aromatic analogues of conduritol F, l-chiro-inositol, and dihydroconduritol F that possess four of the six pancratistatin stereocenters have been synthesized and evaluated for anticancer activity. These compounds serve as truncated pancratistatin analogues lacking the lactam ring B, but retaining the crucial C10a-C10b bond with the correct stereochemistry. The lack of activity of these compounds provides further insight into pancratistatin's minimum structural requirements for cytotoxicity, particularly the criticality of the intact phenanthridone skeleton. Significantly, these series provide rare examples of simple aromatic conduritol and inositol analogues and, therefore, this study expands the chemistry and biology of these important classes of compounds.

Total Syntheses of Pancratistatin. A Review

“…Recently, Kornienko and coworkers 36 synthesized ring B opened analogues 8a–e , 9a–e and 10a–e , which possess this essential C10a – C10b bond with the correct stereochemistry (Fig. 4).…”

Total synthesis of (−)-petrosiol E

“…7 The primary alcohol 10 was transformed into alkyl iodide 11 (Scheme 2) and then the intermediate was treated with neat PPh 3 at 100 C to deliver the phosphonium salt 9 in 96% overall yield for three steps. The known MOM-protected D-xylose derivative 8 was prepared from D-xylose according to a published procedure 6 in 62% of overall yield for three steps. Wittig olefination of the hemiacetal 8 and the phosphonium salt 9 was thus pursued.…”

“…The key intermediate 6 could be obtained from alkene 7 via a multi-step sequence: hydrogenation of alcohol 7, followed by oxidation, Wittig reaction, and baseinduced elimination would furnish the desired 1-bromoalkyne 6. Alkene 7 could be obtained by chain elongation of the known MOM-protected D-xylose 8 6 with the phosphonium salt 9, which could be accessible readily from D-xylose and 11-bromoundecanol, respectively. Taking advantages of its excellent stabilities under strong base treatment and Pd-catalyzed hydrogenation conditions, methoxymethyl (MOM) was selected to protect hydroxyl groups of D-xylose and could be removed eventually under acid conditions.…”

Unnatural C-1 homologues of pancratistatin — Synthesis and promising biological activities

“…3 More recently, however, the studies of these natural products have shifted toward the investigation of unnatural derivatives that would offer the potential of better bioavailability than the rather insoluble natural products. In the last two decades, many reports have appeared describing the synthesis and evaluation of truncated derivatives from the groups of Pettit, 4 McNulty, 5 Kornienko, 6 Chapleur, 7 Alonso, 8 Marion, 9 Banwell, 10 and Gonzalez. 11 Truncated derivatives of the core of these constituents as well as various heteroatom analogues have been reported and some of these compounds displayed various levels of biological activity, usually of lower potency than the natural products.…”