ABSTRACT
The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency. The structurally simplified macrocycles are accessible in 12 steps from readily available indolin-2-one and tert-leucine with excellent diastereoselectivity (99:1 dr) in the key macrocyclization step. The most potent macrocycle acts as a tubulin assembly inhibitor and exerts similar effects on A2058 cell cycle progression and induction of apoptosis as does marketed microtubule-targeting agent vinorelbine.
Subject(s)
Antineoplastic Agents , Apoptosis , Microtubules , Tubulin Modulators , Humans , Tubulin Modulators/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/chemical synthesis , Cell Line, Tumor , Microtubules/drug effects , Microtubules/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Structure-Activity Relationship , Cell Proliferation/drug effects , Cell Cycle/drug effects , Biological Products/pharmacology , Biological Products/chemistry , Biological Products/chemical synthesis , Drug Screening Assays, Antitumor , Stereoisomerism , Tubulin/metabolism , Tubulin/chemistry , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings , OxazolesABSTRACT
Stereoselective synthesis of the right-hand heteroaromatic macrocycle of diazonamide A features C16-C18 bond formation in the Suzuki-Miyaura cross-coupling and atropodiastereoselective Dieckmann-type macrocyclization as key steps. The Suzuki-Miyaura cross-coupling gave the best yields when it was catalyzed by a palladium-dioxygen complex.
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Oxazoles/chemical synthesis , Crystallography, X-Ray , Heterocyclic Compounds, 4 or More Rings/chemistry , Macrocyclic Compounds/chemistry , Models, Molecular , Molecular Structure , Oxazoles/chemistry , StereoisomerismABSTRACT
Hydroxymethylation of cyclic tert-butanesulfinylketimine-derived lithium enamides with methoxymethanol proceeds with excellent diastereoselectivity (99:1 dr). Methoxymethanol is a stable and easy-to-handle source of anhydrous monomeric formaldehyde in the reaction with lithium enamides. Cyclic α-hydroxymethyl ketimines undergo highly diastereoselective reduction to syn- or anti-1,3-amino alcohols.
