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1.
ACS Med Chem Lett ; 11(8): 1634-1644, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32832034

RESUMO

Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/ß-catenin signaling.

2.
Chem Sci ; 11(42): 11570-11578, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34094403

RESUMO

Maleidrides are a class of bioactive secondary metabolites unique to filamentous fungi, which contain one or more maleic anhydrides fused to a 7-, 8- or 9- membered carbocycle (named heptadrides, octadrides and nonadrides respectively). Herein structural and biosynthetic studies on the antifungal octadride, zopfiellin, and nonadrides scytalidin, deoxyscytalidin and castaneiolide are described. A combination of genome sequencing, bioinformatic analyses, gene disruptions, biotransformations, isotopic feeding studies, NMR and X-ray crystallography revealed that they share a common biosynthetic pathway, diverging only after the nonadride deoxyscytalidin. 5-Hydroxylation of deoxyscytalidin occurs prior to ring contraction in the zopfiellin pathway of Diffractella curvata. In Scytalidium album, 6-hydroxylation - confirmed as being catalysed by the α-ketoglutarate dependent oxidoreductase ScyL2 - converts deoxyscytalidin to scytalidin, in the final step in the scytalidin pathway. Feeding scytalidin to a zopfiellin PKS knockout strain led to the production of the nonadride castaneiolide and two novel ring-open maleidrides.

3.
Chem Commun (Camb) ; 51(96): 17088-91, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26452099

RESUMO

The filamentous fungus Byssochlamys fulva strain IMI 40021 produces (+)-byssochlamic acid 1, its novel dihydroanalogue 2 and four related secondary metabolites. Agnestadrides A, 17 and B, 18 constitute a novel class of seven-membered ring, maleic anhydride-containing (hence termed heptadride) natural products. The putative maleic anhydride precursor 5 for both nonadride and heptadride biosynthesis was isolated as a fermentation product for the first time and its structure confirmed by synthesis. Acid 5 undergoes facile decarboxylation to anhydride 6. The generic term maleidrides is proposed to encompass biosynthetically-related compounds containing maleic anhydride moieties fused to an alicyclic ring, varying in size and substituents.


Assuntos
Byssochlamys/metabolismo , Furanos/metabolismo , Maleatos/metabolismo , Anidridos Maleicos/metabolismo , Furanos/química , Maleatos/química , Anidridos Maleicos/química , Estrutura Molecular
4.
Bioorg Med Chem ; 22(15): 4298-311, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24909677

RESUMO

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD7.4 <5.3 and CLND solubility >116 µg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD7.4 (2.4), high LE (0.43), and solubility (152 µg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.


Assuntos
Benzimidazóis/química , Receptores CCR4/antagonistas & inibidores , Sulfonamidas/química , Compostos Aza/química , Humanos , Indazóis/química , Ligação Proteica , Receptores CCR4/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
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