Karl J. Hale

The chemistry and biology of the bryostatin antitumour macrolides

This review summarises the main developments that have occurred in bryostatin chemistry over the period 1982 to 2001 and has 117 references.

Agelastatin A: a novel inhibitor of osteopontin-mediated adhesion, invasion, and colony formation

Effective inhibitors of osteopontin (OPN)–mediated neoplastic transformation and metastasis are still lacking. (-)-Agelastatin A is a naturally occurring oroidin alkaloid with powerful antitumor effects that, in many cases, are superior to cisplatin in vitro. In this regard, past comparative assaying of the two agents against a range of human tumor cell lines has revealed that typically (-)-agelastatin A is 1.5 to 16 times more potent than cisplatin at inhibiting cell growth, its effects being most pronounced against human bladder, skin, colon, and breast carcinomas. In this study, we have investigated the effects of (-)-agelastatin A on OPN-mediated malignant transformation using mammary epithelial cell lines. Treatment with (-)-agelastatin A inhibited OPN protein expression and enhanced expression of the cellular OPN inhibitor, Tcf-4. (-)-Agelastatin A treatment also reduced β-catenin protein expression and reduced anchorage-independent growth, adhesion, and invasion in R37 OPN pBK-CMV and C9 cell lines. Similar effects were observed in MDA-MB-231 and MDA-MB-435s human breast cancer cell lines exposed to (-)-agelastatin A. Suppression of Tcf-4 by RNA interference (short interfering RNA) induced malignant/invasive transformation in parental benign Rama 37 cells; significantly, these events were reversed by treatment with (-)-agelastatin A. Our study reveals, for the very first time, that (-)-agelastatin A down-regulates β-catenin expression while simultaneously up-regulating Tcf-4 and that these combined effects cause repression of OPN and inhibition of OPN-mediated malignant cell invasion, adhesion, and colony formation in vitro. We have also shown that (-)-agelastatin A inhibits cancer cell proliferation by causing cells to accumulate in the G2 phase of cell cycle. [Mol Cancer Ther 2008;7(3):548–58]

A practical new asymmetric synthesis of (2S,3S)- and (2R,3R)-3-hydroxyleucine

Abstract A convenient new asymmetric synthesis of both enantiomers of erythro-3-hydroxyleucine is described. The key steps involve Sharpless asymmetric dihydroxylation (AD) of α,β-unsaturated ester 3, cyclic sulphate formation from the resulting diol, SN2 reaction with sodium azide, deesterification with aqueous sodium hydroxide, and hydrogenolysis. Utilising this route, (2S,3S)-(+)-3-hydroxyleucine (1) was obtained in 97% ee and 67% overall yield; the (2R,3R)-(−)-enantiomer was isolated in 92% ee and 57% overall yield.

Azinothricin synthetic studies. 1. Efficient asymmetric synthesis of (3R)- and (3S)-piperazic acids

Abstract A convenient asymmetric synthesis of both ( 3R )- and ( 3S )-piperazic acids has been developed that is based on electrophilic hydrazination of a chiral bromovaleryl carboximide enolate with di- tert -butyl azodicarboxylate, followed by subsequent intramolecular S N 2 displacement of the bromide by the resulting substituted aza anion. The diastereoselectivity of the process is typically greater than 96%.

Biosynthetic Chlorination of the Piperazate Residue in Kutzneride Biosynthesis by KthP

Kutznerides 2 and 8 of the cyclic hexadepsipeptide family of antifungal natural products from the soil actinomycete Kutzneria sp. 744 contain two sets of chlorinated residues, a 6,7-dichlorohexahydropyrroloindole moiety derived from dichlorotryptophan and a 5-chloropiperazate moiety, as well as a methylcyclopropylglycine residue that may arise from isoleucine via a cryptic chlorination pathway. Previous studies identified KtzD, KtzQ, and KtzR as three halogenases in the kutzneride pathway but left no candidate for installing the C5 chlorine on piperazate. On the basis of analysis of the complete genome sequence of Kutzneria, we now identify a fourth halogenase in the pathway whose gene is separated from the defined kutzneride cluster by 12 open reading frames. KthP (kutzneride halogenase for piperazate) is a mononuclear nonheme iron halogenase that acts on the piperazyl ring tethered by a thioester linkage to the holo forms of thiolation domains. MS analysis of the protein-bound product confirmed chlorination of the piperazate framework from the (3S)- but not the (3R)-piperazyl-S-pantetheinyl thiolation proteins. After thioesterase-mediated release, nuclear magnetic resonance was used to assign the free imino acid as (3S,5S)-5-chloropiperazate, distinct from the 3S,5R stereoisomer reported in the mature kutznerides. These results demonstrate that a fourth halogenase, KthP, is active in the kutzneride biosynthetic pathway and suggest further processing of the (3S,5S)-5-chloropiperazate during subsequent incorporation into the kutzneride depsipeptide frameworks.

Anomalous enantioselectivity in the Sharpless catalytic asymmetric dihydroxylation reaction of 1,1-disubstituted allyl alcohol derivatives

Abstract The Sharpless asymmetric dihydroxylation (AD) reaction has been examined on a number of 1,1-disubstituted allyl alcohol derivatives. In the majority of substrates studied, the product diols had ees in the 11–91% range and had absolute stereochemistry opposite to that predicted using the Sharpless steric model.

Total Synthesis of (+)-Azinothricin and (+)-Kettapeptin

Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final stages of both respective syntheses.

Monamycin synthetic studies. Pt 1. An enantiospecific total synthesis of (3S,5S)-5-hydroxypiperazic acid from D-mannitol

Abstract The first enantiospecific total synthesis of (3 S ,5 S )-hydroxypiperazic acid 1 is described. The synthesis begins from D-mannitol and exploits a tandem electrophilic hydrazination/nucleophilic cyclisation reaction to assemble the hexahydropyridazine ring system.

Synthetic studies on the azinothricin family of antibiotics. 2. Asymmetric synthesis of the C(28)–C(47) subunit of A83586C

Abstract An asymmetric synthesis of the C(28)–C(47) segment of the antitumour antibiotic A83586C is described.

Asymmetric total synthesis of (+)-inthomycin C via O-directed free radical alkyne hydrostannation with Ph3SnH and catalytic Et3B: reinstatement of the Zeeck-Taylor (3R)-structure for (+)-inthomycin C.

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (-)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (-)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyamas (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylors original (3R)-stereostructure for (+)-inthomycin C is correct.