The total syntheses of the potent antiviral agent
(−)-macrolactin A (1) and two related family
members, (+)-macrolactin E (5) and (−)-macrolactinic
acid (7), have been achieved, exploiting a
unified,
convergent, and highly stereocontrolled strategy. Extensive use of
the palladium-catalyzed Stille cross-coupling
reaction for the stereospecific construction of the three isolated
dienes including macrocyclization formed the
cornerstone of the successful strategy. The total syntheses of
these natural products, no longer available via
fermentation, confirm their relative and absolute stereochemistries and
provide access to possible analogues
for further biological study.
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.
A series of novel 7-amino-1, 3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.
Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.
A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.
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