A5051741667- Synthetic Organic Chemistry Methods
- DNA Repair Mechanisms
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Chemical Synthesis and Reactions
- Marine Sponges and Natural Products
- PARP inhibition in cancer therapy
- Steroid Chemistry and Biochemistry
- Hormonal Regulation and Hypertension
- Advanced biosensing and bioanalysis techniques
- Cancer therapeutics and mechanisms
- Synthesis and Reactions of Organic Compounds
- Organic Chemistry Cycloaddition Reactions
- Organic Chemistry Synthesis Methods
- Oxidative Organic Chemistry Reactions
- Pharmacogenetics and Drug Metabolism
- Synthesis and Catalytic Reactions
- RNA and protein synthesis mechanisms
- CRISPR and Genetic Engineering
Cancer Research UK
2021
Imperial College London
2012-2014
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining, without targeting Non-Homologous Joining. In addition, elicits damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation screening revealed that...
Human DNA polymerase theta (Polθ), which is essential for microhomology-mediated double strand break repair, has been proposed as an attractive target the treatment of BRCA deficient and other repair pathway defective cancers. As previously reported, we recently identified first selective small molecule Polθ in vitro probe, 22 (ART558), recapitulates phenotype loss, vivo 43 (ART812), efficacious a model PARP inhibitor resistant TNBC vivo. Here describe discovery, biochemical biophysical...
This article describes a robust and large-scale synthesis of the ketosteroid building block 11β-hydroxyandrosterone (2) from cheap readily available hydrocortisone (1). The initial discovery route, which was conducted on gram scale achieved 3–6% yield over eight steps, is also described. Key to route redesign incorporation two stereoselective steps setting desired 5α-H 3α-OH chiral centers optimization minimize chromatographic purification. process then at kilogram 21–28% four steps.
Abstract Biomimetic syntheses of functionalized γ‐resorcylates from 2,2,6‐trimethyl‐4 H ‐1,3‐dioxin‐4‐one derivatives are reported. Cross metathesis 2,2‐dimethyl‐6‐vinyl‐4 with homoallylic esters or aldol reactions tert ‐butyl benzyl 1‐(2,2‐dimethyl‐4‐oxo‐4 ‐1,3‐dioxin‐6‐yl)‐acetone and related ketones followed by aromatization under mild Appel‐type reaction conditions gave a range γ‐resorcylates.
We herein report biomimetic syntheses of 6-substituted salicylates from the cross metathesis 2,2-dimethyl-6-vinyl-1,3-dioxin-4-one with homoallylic alcohols, oxidation, and aromatization intermediate enone–dioxinones. Of particular note is use catalyst 1,4-diazabicyclo[2.2.2]octane in microwave thermolytic ketene generation trapping, cyclization, dehydration reaction sequence.
Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms spiroketal moiety carbon atom. Key steps in synthesis include Meyer-Schuster/Nazarov cascade, hypoiodite mediated oxyfunctionalization, and late-stage installation hydroxyl group on C-ring steroid.
Abstract Isopropyl alkyl and aryl salicylate esters (VI) (X) are prepared by cross metathesis of vinyl dioxinone (II) with homoallylic alcohols (I) (VII), resp., followed oxidation aromatization via generation trapping enedione‐ketenes.
Abstract To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight, allosteric inhibitors of the polymerase function Theta (Polθ), including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous Joining. Moreover, show that exposure to can elicit damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation...
Abstract To target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining (TMEJ), without targeting Non-Homologous Joining. Moreover, show that exposure to can elicit damage and synthetic lethality BRCA1- or BRCA2-mutant tumor cells enhances effects a PARP inhibitor. Genetic perturbation screening...