Advances in developing noncovalent small molecules targeting Keap1

Kelch-like ECH-associated protein 1 (Keap1) is a drug target for diseases involving oxidative stress and inflam-mation. There are three covalent Keap1-binding drugs on the market, but noncovalent compounds that inhibit the interaction between Keap1 and nuclear factor erythroid 2 -related factor 2 (Nrf2) represent an attractive alternative. Both compound types prevent degradation of Nrf2, lead-ing to the expression of antioxidant and antiinflammatory proteins. However, their off-target profiles differ as do their exact pharmacodynamic effects. Here, we discuss the opportunities and challenges of targeting Keap1 with covalent versus noncovalent inhibitors. We then provide a comprehensive overview of current noncovalent Keap1-Nrf2 inhibitors, with a focus on their pharmacological effects, to examine the therapeutic potential for this compound class

Synthesis and Antiproliferative Activity of [1,2,4]triazino[4,3-a]indoles

A series of [1,2,4]triazino[4,3-a]indoles was prepared in good yield by reacting 2-diazo-3-ethoxycarbonylindole with methylene active compounds. Derivatives of the title ring system were tested against a panel of 60 human tumor cell lines, and showed inhibitory activity against a wide range of cancer cell lines at micromolar concentration

Docking of indolo- and pyrrolo-pyrimidines to DNA. New DNA-interactive polycycles from amino-indoles/pyrroles and BMMA.

New indolo- and pyrrolo-pyrimidines of type 1-4 were studied for their ability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -8.39 ÷ -16.72 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs whereas the side chain lies along the minor groove

Marine anticancer agents: An overview with a particular focus on their chemical classes

UID/Multi/04378/2019 IF/00700/2014 grant number 216Z167 grant RTA 2015-00010-C03-02 No. PBA/MB/16/01 PDOC/19/02/01The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.publishersversionpublishe

Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones

A series of substituted 3-(4-nitrophenyloxy)methylindole-4,7-diones (Q) were synthesised. The effects of substitution patterns on the indole core on rates of elimination of 4-nitrophenol as a model for drug release following fragmentation of a phenolic ether linker were studied. After reduction to either the radical anion (Q ؒϪ ) or hydroquinone (QH 2 ) elimination of 4-nitrophenol occurred from the (indol-3-yl)methyl position. The half-lives , typical of tumour hypoxia, were t1 -2 ≈ 0.3-1.8 ms, the higher values associated with higher reduction potentials. Half-lives for the autoxidation of the QH 2 were markedly longer at the same oxygen concentration (t1 -2 ≈ 8-102 min) and longer still in the presence of 4 µmol dm Ϫ3 superoxide dismutase (t1 -2 ≈ 8-19 h). Although the indolequinones were able to eliminate 4-nitrophenol with high efficiency only Q ؒϪ radicals of the 3-carbinyl substituted derivatives did so with sufficiently short half-lives (t1 -2 ≈ 41-2 ms) to compete with electron transfer to oxygen and therefore have the potential to target the leaving group to hypoxic tissue. The hydroquinones are not sufficiently oxygen sensitive to prevent the elimination of 4-nitrophenol (t1 -2 ≈ 1.5-3.5 s) even at oxygen concentrations expected in normal tissue. By incorporating electron rich substituents at the indolyl carbinyl position it is possible to control the rate of reductive fragmentation. This may prove an important factor in the design of an indolequinone-based bioreductive drug delivery system

4,5,6,9-tetraidropirrolo[2',3':3,4] cicloepta[1,2-d] isossazoli, procedimento per la loro produzione e loro uso come antitumorali

La presente invenzione riguarda derivati a struttura 4,5,6,9- tetraidropirrolo[2',3':3,4]cicloepta[1,2-d]isossazolica, procedimenti per la loro produzione e il loro uso per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica. I nuovi derivati saggiati al National Cancer Institute di Bethesda su un pannello di circa 60 linee cellulari umane divise in 9 sottopannelli (mammella, ovaie, polmone, colon, SNC, melanoma, leucemia, rene, prostata), hanno mostrato attività antiproliferativa da micro a nanomolare, rivelando alcuni derivati particolarmente promettent

Composti a struttura ossazolica, procedimenti per la loro produzione e loro impiego per la cura di patologie a carattere iperproliferativo

La presente invenzione riguarda composti che presentano nella loro struttura il sistema eterociclico [1,2]Ossazolo[5,4-e]isoindolo, un procedimento per la oro produzione e il loro impiego per la cura di patologie a carattere iperproliferativo comprese quelle di natura neoplastica. I nuovi derivati saggiati al National Cancer Institute di Bethesda su un 60 linee cellulari umane divise in 9 sottopannelli (mammella, ovaie, polmone, colon, SNC, melanoma, leucemia, rene, prostata), hanno mostrato attività antiproliferativa da micro a nanomolare, rivelando alcuni derivati particolarmente promettenti

4,5,6,9-TETRAHYDROPYRROLO[2',3'-3,4]CYCLOEPTA[1,2-d]ISOSSAZOLE, PROCESS FOR THEIR PRODUCTION AND THEIR USES AS ANTITUMOR AGENTS

The present invention concerns the synthesis of compounds bearing the PYRROLO[2',3'-3,4]CYCLOEPTA[1,2-d]ISOSSAZOLE structure, and their use for the treatment of pathologies having hyperproliferative features included those having neoplastic nature

NUOVI AGENTI TERAPEUTICI PER IL TRATTAMENTO DI PATOLOGIE EMATOLOGICHE

La presente invenzione si riferisce al campo di nuove molecole tetracicliche, aventi un sistema tetraciclico, e loro impiego come medicamenti di patologie ematologiche in particolare per il trattamento della leucemia mieloide acuta (AML) in pazienti emizigoti FLT3/ITD resistenti alle terapie convenzionali