Studies toward the Synthesis of an Oxazole-Based Analog of (−)-Zampanolide

Bold, Christian Paul; Klaus, Cindy; Pfeiffer, Bernhard; Schürmann, Jasmine; Lombardi, Rafael; Lucena‐Agell, Daniel; Díaz, J. Fernando; Altmann, Karl‐Heinz

doi:10.1021/acs.orglett.1c00378

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…The importance of the C17‐methyl group was confirmed by recent work by the Altmann lab [11b] . Moreover, the role of the C17‐methyl group as a conformational controlling element is in agreement their previous studies of des‐tetrahydropyran [12] and oxazole [13] analogues.…”

Section: Introductionsupporting

confidence: 90%

Linear (−)‐Zampanolide: Flexibility in Conformation–Activity Relationships

Umaña,

Henry,

Saltzman

et al. 2023

ChemMedChem

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Through an understanding of the conformational preferences of the polyketide natural product (−)‐zampanolide, and the structural motifs that control these preferences, we developed a linear zampanolide analogue that exhibits potent cytotoxicity against cancer cell lines. This discovery provides a set of three structural handles for further structure‐activity relationship (SAR) studies of this potent microtubule‐stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.

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Section: Introductionsupporting

confidence: 90%

Linear (−)‐Zampanolide: Flexibility in Conformation–Activity Relationships

Umaña,

Henry,

Saltzman

et al. 2023

ChemMedChem

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“…A characteristic example for the other methodologies is the reaction between benzaldehydes, with 4-phenyl-thiosemicarbazide involving a hydrazone intermediate which reacts with benzoin to obtain 2-oxazolines [28]; another methodology is based on the (3 + 2) reaction between TosMIC 5 and an aromatic aldehyde in the presence of a base. This synthetic strategy generally leads to the corresponding oxazole via the oxidation of the primary oxazoline formed [36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles

Tlapale-Lara,

López,

Gómez

et al. 2024

IJMS

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The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.

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“…[7][8][9] Synthetic work has also been expended on a variety of analogs of 1 in the context of structure-activity relationship (SAR) studies. This has included investigations of modifications of the C(19)-side chain, [6,10,11] the tetrahydropyran ring, [10,[12][13][14][15][16][17] and, most recently, the macrolide backbone. [18,19] As part of these studies, work in our own laboratory has revealed that 13-desmethylene-(−)zampanolide (2) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure-Activity Relationship Studies of Dioxane- and Oxathiane-Based Analogs of (–)-Zampanolide

Cotter,

Glauser,

Lelke

et al. 2024

Preprint

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We have prepared a series of analogs of the complex marine macrolide (–)-zampanolide, which incorporate a dioxane-, oxathiane-, or oxathiane-dioxide ring in place of the natural tetrahydropyran moiety and we have determined their microtubule-binding affinity and antiproliferative activity against human cancer cells. The synthesis of these analogs was based on a convergent strategy with a HWE-based macrocyclization and a stereoselective aza-aldol reaction as key steps. The microtubule-binding affinity and cellular potency of the dioxane- and oxathiane-based analogs with a natural (Z,E)-sorbamide-based side chain were essentially indistinguishable from those of natural (–)-zampanolide; changing the configuration of the sorbamide unit from Z,E to E,E resulted in a slight loss in activity. In contrast, the presence of an oxathiane-dioxide ring caused a steep decrease in microtubule-binding and a significant loss in growth inhibitory activity. In addition, a substantial loss in potency was observed against a multidrug-resistant, P-glycoprotein-overexpressing cell line, while no such effect was found for the dioxane- or oxathiane-based analogs. A high-resolution X-ray crystal structure of the complex between beta-tubulin and dioxane-zampanolide was obtained, which showed that this compound, like natural (–)-zampanolide, induces helical structuring of the M-loop.

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Studies toward the Synthesis of an Oxazole-Based Analog of (−)-Zampanolide

Cited by 8 publications

References 35 publications

Linear (−)‐Zampanolide: Flexibility in Conformation–Activity Relationships

Linear (−)‐Zampanolide: Flexibility in Conformation–Activity Relationships

Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles

Synthesis and Structure-Activity Relationship Studies of Dioxane- and Oxathiane-Based Analogs of (–)-Zampanolide

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