Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs
Abstract
We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (-)-zampanolide (ZMP). These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67-95 % yield) and a stereoselective aza-aldol reaction with an (S)-BINOL-derived sorbamide transfer complex, to establish the C(20) stereocenter (24-71 % yield). As the sole exception, for the 5-desmethyl macrocycle, ring-closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule-binding affinity compared to DM-ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50 values for cancer cell growth inhibition varied between 5 and 133 nM, compared to 1-12 nM for DM-ZMP. Reduction of the enone double bond led to a several hundred-fold loss in growth inhibition. The cellular potency of 2,3-dihydro-13-desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM-ZMP. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000614717Publication status
publishedExternal links
Journal / series
Chemistry - A European JournalVolume
Pages / Article No.
Publisher
Wiley-VCHSubject
medicinal chemistry; natural products; structure-activity relationships; total synthesis; zampanolideOrganisational unit
03647 - Altmann, Karl-Heinz (emeritus) / Altmann, Karl-Heinz (emeritus)
Funding
149253 - Natural Products as Lead Structures for Anticancer and Antibacterial Drug Discovery: SAR Evaluation of Zampanolide and Pyridomycin (SNF)
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