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Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.

// Gordon W. Rewcastle 1, 2 , Sharada Kolekar 3 , Christina M. Buchanan 2, 3 , Swarna A. Gamage 1 , Anna C. Giddens 1 , Kit Y. Tsang 1 , Jackie D. Kendall 1, 2 , Ripudaman Singh 1 , Woo-Jeong Lee 3 , Greg C. Smith 4 , Weiping Han 5 , David J. Matthews 6 , William A. Denny 1, 2 , Peter R. Shepherd 2, 3 and Stephen M.F. Jamieson 1, 2, 7 1 Auckland Cancer Society Research Centre, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand 2 Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand 3 Department of Molecular Medicine and Pathology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand 4 Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, Australia 5 Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore 6 PharmIntuition, San Francisco, CA, USA 7 Department of Pharmacology and Clinical Pharmacology, School of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand Correspondence to: William A. Denny, email: b.denny@auckland.ac.nz Keywords: SN32976, phosphatidylinositol 3-kinase, pan PI3K inhibitor, PI3Kα-preferential, kinase selectivity Received: January 31, 2017 Accepted: April 14, 2017 Published: May 09, 2017 ABSTRACT Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity.

Replacement of one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 (1) with sulfonamide containing substituents produced a new class of active and potent PI3Kα inhibitors. Solubility issues prevented all but the 6-amino derivative 17 from being evaluated in vivo, but the clear activity of this compound demonstrated that this class of PI3K inhibitor shows great promise.

As part of our investigation into the pyrazolo[1,5-a]pyridines as novel PI3K inhibitors, we report a range of analogues where the central linker portion of the molecule was varied while retaining the pyrazolo[1,5-a] pyridine and arylsulfonyl or arylcarbonyl groups. Isostere generating software BROOD was used to assist with producing ideas. The isoform selectivity of the compounds varied from pan-PI3K for compound 41 to p110a-selective for compound 58 or p110d-selective for compound 57. The latter two compounds varied only in their sulphur oxidation state.

As part of our investigation into pyrazolo[1,5-a]pyridines as novel p110α selective PI3 kinase inhibitors, we report a range of analogues with improved aqueous solubility by the addition of a basic amine. The compounds demonstrated comparable p110α potency and selectivity to earlier compounds but with up to 1000× greater aqueous solubility, as the hydrochloride salts. The compounds also displayed good activity in a cellular assay of PI3 kinase activity.

Structure-activity relationship studies of the pyrazolo[1,5-a]pyridine class of PI3 kinase inhibitors show that substitution off the hydrazone nitrogen and replacement of the sulfonyl both gave a loss of p110α selectivity, with the exception of an N-hydroxyethyl analogue. Limited substitutions were tolerated around the phenyl ring; in particular the 2,5-substitution pattern was important for PI3 kinase activity. The N-hydroxyethyl compound also showed good inhibition of cell proliferation and inhibition of phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity. It had suitable pharmacokinetics for evaluation in vivo, and showed tumour growth inhibition in two human tumour cell lines in xenograft studies. This work has provided suggestions for the design of more soluble analogues. © 2011 Elsevier Ltd. All rights reserved.

(1, Scheme 1), the prototypical member of astructurally related family of antibiotics known as therubromycins, consists of a densely oxygenated naphthazarinring and an isocoumarin moiety linked through a uniquearomatic 5,6-spiroketal ring system (Scheme 1). The rubro-mycins exhibit a wide range of biological activity includingantimicrobialandanticancerproperties.

The synthesis of a series of aromatic 5,6-benzannelated and naphthyl-benzannelated spiroacetals related to the spiroacetal unit present in the quinonoid antibiotic γ-rubromycin is reported. The key steps include the use of Sonogashira coupling to construct an aryl acetylene that is coupled to an aryl aldehyde forming a propargyl alcohol intermediate. Hydrogenation of the resultant alkynol followed by oxidation produces a masked dihydroxyketone that upon treatment with silica-supported sodium hydrogen sulfate undergoes concomitant deprotection and cyclisation to afford the desired fused aromatic spiroacetal.

The facile synthesis of a series of aromatic 6,6-spiroacetals based on the parent 3,4,3′,4′-tetrahydro-2,2′-spirobis(2H-1-benzopyran) heterocyclic system is reported. Key steps included the use of a Sonogashira coupling for the synthesis of an aryl acetylene that was coupled to an aryl aldehyde to form a propargyl alcohol intermediate. Hydrogenation of the alkynol followed by oxidation produced a masked dihydroxy ketone that upon treatment with trimethylsilyl bromide underwent deprotection and cyclisation to the fused aromatic spiroacetal.

The crystal structure of the title compound, C21H18O3, has been determined to establish the relative stereochemistry at the spiro ring junction. Each O atom adjacent to the junction lies axial to the neighbouring ring; this is presumably due to anomeric effects.

The crystal structure of the title compound, C18H18O4, has been investigated to establish the relative stereochemistry at the spiro ring junction. Each of the O atoms adjacent to the junction is an axial substituent of the neighboring ring; the adoption of this conformation is likely to be due to anomeric effects.

The crystal structure of the title compound, C17H16O3, has been determined to establish the relative stereochemistry at the spiro ring junction. Both O atoms adjacent to the junction adopt axial positions because of anomeric effects.

In the crystal structure of the title compound, C16H16O6, a pair of naphthoquinone rings are linked via O—H...O—C hydrogen bonds in a nearly orthogonal arrangement. This dimeric unit is linked to a neighbouring dimer by π–π stacking interactions between the naphthoquinone rings, where the distance between the mean plane of the naphtoquinone backbones is 3.468 Å, and O—H...O—C hydrogen bonds.