Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

Abstract

A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred-fold less potent than 1.

High affinity and covalent-binding microtubule stabilizing agents show activity in chemotherapy-resistant acute myeloid leukemia cells

“…Zampanolide was synthetized following the procedure described by Zurwerra et al [14]. Paclitaxel and vinblastine were obtained from Sigma, and cytarabine and daunorubicin were obtained from the Memorial Sloan Kettering Cancer Center pharmacy.…”

Zampanolide and dactylolide: cytotoxic tubulin-assembly agents and promising anticancer leads

“…The C20-epimer of 1 ( 5 ) and the bis-amide by-product ( 6 ) 11,17,24 are about one order of magnitude less potent than 1 in all the cell lines examined. Altmann's analogs 7 , 11 , and 12 showed comparable activity to that of 3 , suggesting that neither the aldehyde functionality nor the 13-methylene group are essential for the relatively weak antiproliferative activity of 3 .…”

“…Altmann's analogs 7 , 11 , and 12 showed comparable activity to that of 3 , suggesting that neither the aldehyde functionality nor the 13-methylene group are essential for the relatively weak antiproliferative activity of 3 . 17 Conversion of the C20-hydroxyl group in 7 to the C20-methoxyl group in 8 leads to a 14-fold loss in antiproliferative potency. Carboxylic acid 9 is significantly less potent than the corresponding primary alcohol 7 .…”

“…17,82 The requisite precursor would be obtained via ester formation between the C1–C8 fragment ( 183 ) and the C9–C20 fragment ( 184 ). The synthesis of the C9–C20 fragment 184 started with the Cu-mediated regioselective epoxide opening of 185 , prepared from ( R )-aspartic acid in three steps, with vinyl-MgBr (Scheme 40).…”

Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities

“…Interestingly, one analogue that is devoid of the entire tetrahydropyran ring, yet maintains the hemiaminal side chain retains biological activity. 82 The ability of zampanolide to bind covalently to microtubules was identified in a collaborative effort led by Fernando Diaz 83 and is described in detail below in comparison with other microtubule stabilizers and their interactions with tubulin binding sites.…”