A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the...

This review presents an overview of 1 → 2 branched dendrimers and dendrons, created by a divergent procedure, from their synthesis to modern day applications. The first members of this branched class of fractal macromolecules were prepared through a cascade synthesis, which was later replaced b...

Pre-swinholide A (1a), the monomeric carboxylic acid of swinholide A (2) has been isolaled from a sponge collected in Papua New Guinea. Its stereochemistry matches the absolute chirality recently established for 2.

The C19-C32 segment 10 of swinholide A was prepared in 15 steps (8% yield, 82% ds) from (±)-16. Key steps include (i) the Sharpless epoxidation, 16 → 17, (ii) the acetal allylation, 15 → 23, (iii) the anti aldol addition, 13 + 14 → 12, and (iv) the alkene hydroboration, 30 → 31. The swinhol...

Swinholide A and isoswinholide A were synthesised in 7 steps from the fully protected seco acid 4. Key steps include: (i) bimolecular acylation, 7 + 10 → 12, (ii) selective hydrolysis of the methyl ester, 16 → 17, and (iii) regioselective macrolactonisation. 17 → 18. The monomeric lactone ana...

Two coupling strategies for (−)-pre-swinholide A were devised based on the analysis in Scheme 1. In the first route, a boron-mediated aldol reaction between the ethyl ketone 19 and the aldehyde 3 was used to construct the C15-C16 bond with moderate diastereoselectivity. In the second route, a Mu...

The aldehyde 8, a C1-C15 subunit of swinholide A, was prepared in 10 steps (14.5% yield, 78% ds) by starting with the asymmetric aldol reaction, 15 + 17 → 18. Conversion into the corresponding ethyl ketone 9 provides a C1-C15 subunit of scytophycin C.

SummaryMarine toxins targeting the actin cytoskeleton represent a new and promising class of anti-cancer compounds. Here we present a 2.0 Å resolution structure of swinholide A, a marine macrolide, bound to two actin molecules. The structure demonstrates that the actin dimer in the complex does ...

The fully protected monomeric unit 19 of the marine macrodiolide, swinholide A (1), was obtained with > 97% ds by a Mukaiyama aldol reaction between 16 and 5, followed by a boron-mediated reduction to give the syn 1,3-diol 18. Deprotection gave (−)-pre-swinholide A (2), the putative biosynthetic...

An efficient and highly stereoselective construction of the C(9)–C(17) dihydropyran segment of swinholides A–C, which involves a novel reductive cleavage of an epoxy aldehyde by an organoselenium reagent and the intramolecular conjugate addition of an acetal alkoxide anion of δ-hydroxy-α,β-...

Chemical investigation of an Indonesian specimen of Theonella swinhoei afforded the new dimeric macrolides isoswinholide B (5) and swinholide K (6), along with the known swinholides A (1), B (2) and D (3) and isoswinholide A (4). Isoswinholide B showed an unprecedented 21/19′ lactonization patt...

Employing an intramolecular Michael addition as a pivotal step, furan 4 has been converted to dioxaspiro compounds 5 and 6, whose heterocyclic frameworks constitute important structural units of 14,15-dihydroprehispanolone 3 and prehispanolone 1, respectively. Hispanolone 2 was converted to 3 as...

On the basis of the recently reported construction of (±)-hispanolone (2), the enantiomerically pure form of (−)-2, employed in our partial synthesis of the specific platelet activating factor receptor antagonist prehispanolone (3), was prepared from (S)-(+)-Wieland-Miescher ketone (1). Moreove...

Employing an intramolecular Michael addition as a pivotal step, butenolide 5, furans 6 and 7 have been converted to dioxaspiro compounds 8, 9, 10 and 11, whose heterocyclic frameworks constitute important structural units of prehispanolone (2) as well as 14,15-dihydroprehispanolones (3) and (4),...

A new labdane diterpene, prehispanolone, has been isolated from Leonurus heterophyllus. Its structure, 9α,13R;15,16-diepoxylabdan-14-en-7-one, was established by spectroscopic means as well as by examination of its derivatives.

The HIV-1 Reverse Transcriptase (RT) is a validated and deeply explored biological target for the treatment of AIDS. However, only drugs targeting the RT-associated DNA polymerase (DP) function have been approved for clinical use. We designed and synthesised a new generation of HIV-1 RT inhibito...

A series of 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were efficiently synthesized by oxidative cyclisation of N′-benzylidene-(1H-indol-3-yl)alkane hydrazides using di(acetoxy)iodobenzene. N′-Benzylidene-(1H-indol-3-yl)alkane hydrazides themselves were derived from simple indo...

A single gene encodes both calcitonin and the calcitonin gene-related peptide (CGRP). Human and rat α-CGRP were compared with sodium nitroprusside in the rat and rabbit isolated mesenteric vascular preparation perfused at constant flow. In the presence of the vasoconstrictor noradrenaline (10−5...

Previous investigations have demonstrated that delayed preconditioning induced by nitroglycerin is mediated by endogenous calcitonin gene-related peptide (CGRP). In the present study, we examined whether CGRP-mediated delayed preconditioning induced by nitroglycerin is involved in activation of ...

Primary headaches may be accompanied by increased intracranial blood flow induced by the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from activated meningeal afferents. We aimed to record meningeal and medullary blood flow simultaneously and to localize the sites of ...