Martin Scobie

Pinacolyl boronic esters as components in the Petasis reaction

The multicomponent reaction of boronic esters with imine or iminium species (generated in situ by reaction of amines with glyoxylic acid) has received little attention in the literature despite the current interest in the corresponding reactions of boronic acids (Petasis reaction). Moreover, the use of boronic esters in this reaction is particularly attractive since chiral esters could act as auxiliaries in a novel enantioselective process. We set out to establish whether boronic esters were general substrates in the Petasis reaction. Pinacolyl boronic esters were selected for study as a model substrate for more complex homochiral boronic esters because of their ease of synthesis and chemical stability. We found that pinacolyl boronic esters do not react with imines derived from primary amines and glyoxylic acid under standard conditions. By contrast, imines derived from secondary amines and glyoxylic acid react readily with vinylboronic esters but less readily with heteroaryl- or arylboronic esters.

Rational design and validation of a Tip60 histone acetyltransferase inhibitor

Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

Summary ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy.

The first example of chiral induction using homochiral boronic esters in the Petasis reaction

Abstract The present study demonstrates the first enantioselective version of the Petasis reaction (boronic Mannich reaction), using glyoxylic acid, morpholine and a homochiral boronic ester as the chiral auxiliary. Chiral boronic esters are readily prepared by condensation of vinylboronic acids and chiral 1,2-diols. In the resulting Petasis reaction, 2-morpholin-1-yl-4-phenylbut-3-enoic acids are formed in high yields and moderate enantioselectivity.

The Synthesis of Some Head to Head Linked DNA Minor Groove Binders

A series of head to head linked dimers of heterocyclic amino acids has been prepared for investigation of affinity and selectivity in binding to the minor groove of DNA. The selection of targets for synthesis was led by computer based design. Several novel dicarboxylic acid linkers including indoles, phenanthrenes, a fluorenone, and a bisbenzothiophene have been included. Analysis of binding to DNA by footprinting showed high affinity for compounds derived from 2,7-dihydrophenanthrene dicarboxylic acid and a predominant selectivity for AT rich regions containing at least 4 AT pairs but with the ability to span up to two CG base pairs.

Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1

The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.

A new concise synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives

A new T3P®-assisted, convenient and efficient procedure for the synthesis of dihydroquinazolinones is described. The main advantages of this protocol include its practical simplicity, short reaction times and particularly the ease with which products are isolated.

Parallel synthesis of unsymmetrically substituted tetraphenyl porphyrins on Wang resin

A method for synthesizing combinatorial libraries of unsymmetrically substituted tetra-meso-phenyl porphyrins on polystyrene based resin is described. Attachment of 5,15-dibromo-10-(4-hydroxyphenyl)-20-(4-nitrophenyl)porphyrin onto brominated Wang resin gave a convenient scaffold for the synthesis of photoactive porphyrin libraries with three points for generating diversity. An array of nine TPP derivatives was prepared by sequential Suzuki coupling/nitro-reduction and acylation protocols.

Application of combinatorial techniques in the synthesis of unsymmetrically substituted 5,15-diphenylporphyrins

Abstract Combinatorial techniques, both solid and solution phase, have been applied to the synthesis of unsymmetrically substituted 5,15-diphenylporphyrins. 5-(4-Hydroxyphenyl)-15-pentafluorophenylporphyrin can be loaded onto solid supports and substituted on the pentafluorophenyl ring with thiols. Diversity is then expanded by cleavage and solution phase substitution of the second phenyl ring using a solid supported base.

A versatile new synthetic route to 1N-hydroxyindazoles.

A new and versatile cyclization reaction affording rare 1N-hydroxyindazoles is presented. Treatment of 2-nitrobenzylamines with methanolic sodium hydroxide furnishes 1N-hydroxyindazoles regioselectively and in high yield. The reaction tolerates a range of functional groups and electronic effects.