An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation

Chen, Guanglin; Gonzalez, Maricarmen; Jiang, Ziran; Zhang, Qiang; Wang, Guangdi; Chen, Qiao‐Hong

doi:10.1016/j.bmcl.2021.127970

Cited by 3 publications

(4 citation statements)

References 16 publications

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“…To this end, we have prepared five analogs of 3/1, including the known C(13)-desmethylene-C(17)-desmethyl-(À )-zampanolide (5), [44] based on a global strategy that we had previously elaborated for the total synthesis of 1 and 3. The successful and efficient preparation of these analogs attests to the robustness of our synthetic approach; in particular, in all cases the intramolecular HWE reaction of phosphono aldehydes 12, which has also been adopted by others, [40][41][42][43][44] provided the desired macrocycles in good yields. In addition, the C(20) stereocenter could be established with high selectivity, employing a putative (S)-BINOL-based amide transfer reagent that we have recently developed.…”

Section: Discussionmentioning

confidence: 78%

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Chemistry A European J

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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.

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Section: Discussionmentioning

confidence: 78%

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Chemistry A European J

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“…To this end, we have prepared six analogs of 3/1, including the known C(13)desmethylene-C(17)-desmethyl-(-)-zampanolide (5), via multi-step syntheses, following a global strategy that we had previously elaborated for the total synthesis of 1 and 3. The successful and efficient preparation of these analogs attests to the robustness of our approach; in particular, the intramolecular HWE reaction of phosphono aldehydes 12, which has also been adopted by others, [40][41][42][43][44] ). According to these computations, all analogs of 3 generally exhibit greater conformational heterogeneity than 1 in the regions surrounding the modifications, but not in other parts of the structure.…”

Section: Discussionmentioning

confidence: 89%

Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

Brütsch

Cotter

Lucena‐Agell

et al. 2023

Preprint

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We have prepared a series of partially reduced or demethylated analogs of the natural microtubule stabilizer (−)-zampanolide and we have assessed their antiproliferative activity, their microtubule-binding affinity and their effects on the cellular microtubule network and on cell cycle progression. For reasons of synthetic efficiency, these analogs were derived from 13-desmethylene-(-)-zampanolide, which we had previously shown to be an equally potent cancer cell growth inhibitor as the natural product. The synthesis of all compounds was based on a unified strategy that included final formation of the macrobicyclic core by an intramolecular HWE reaction and a stereoselective aza-aldol reaction to establish the C(20) stereocenter as the key steps. All structural modifications investigated led to reduced cellular activity and lower microtubule-binding affinity compared to the parent 13-desmethylene-(–)-zampanolide, which may be ascribed to increased conformational flexibility due to the formal reduction of double bonds or the removal of the C(17)-methyl group. Notwithstanding this general trend, the cellular potency of 2,3-dihydro-13-desmethylene zampanolide as the most potent analog identified remained within a 9-fold range of that of 13-desmethylene-(–)-zampanolide (for 5 out of 6 cell lines). Notably, while the formal reduction of the C=C double bond of the enone system that is required for the covalent attachment of (−)-zampanolide to beta-tubulin caused a drop in antiproliferative activity of several hundred fold, the compound does bind to microtubules and shows the typical cellular hallmarks of a microtubule-stabilizing agent.

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“…To take advantage of either of these approaches to improve the therapeutic index of zampanolide, it is critical to first understand its functional pharmacophore and potential chemical liabilities. While the chemically fragile side chain of zampanolide may be a liability, absence of this moiety in the metabolic precursor dactylolide and synthetic mimetics results in compounds with a significant reduction in cellular potency [10,24,25]. In contrast, single digit nanomolar potency can be retained upon replacement of the THP ring of zampanolide with a morpholine, which can serve as a convenient site for modifications to improve physiochemical properties and enhance tumor targeting while retaining binding within the taxane site [26].…”

Section: Discussionmentioning

confidence: 99%

“…Structure-activity relationship studies from zampanolide analogs isolated alongside the natural product demonstrate an unanticipated degree of flexibility in the macrolide core for retaining the potency and mechanism of action of zampanolide [27]. Over 45 analogs of this chemotype have been reported to date (mostly synthetic) [10,18,[24][25][26][27][28] demonstrating that there is potential to modify zampanolide to improve its physiochemical and tumor-targeting properties.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site

et al. 2022

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Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (-)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (-)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.

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An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation

Cited by 3 publications

References 16 publications

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

Synthesis and Structure‐Activity Relationship Studies of C(13)‐Desmethylene‐(−)‐Zampanolide Analogs

Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(−)-Zampanolide Analogs

In Vivo Evaluation of (−)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site

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