77960-29-3

Upstream product

• 98-01-1 furfural 
• 4439-53-6 N-benzyl(furan-2-ylmethyl)amine 
• 100-46-9 benzylamine 
• 1212092-04-0 3-benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.0*1,5*]dec-8-ene-6-carboxylic acid 

Downstream Products

• 77960-30-6 methyl N-benzyl-2,3-dihydro-3-oxo-1H-isoindole-4-carboxylate 
• 1390623-34-3 ZIN⁽⁰³⁸⁾C₀₀₅₉₄ 
• 1390623-33-2 (S)-1-(2-benzyl-3-oxoisoindoline-4-carbonyl)pyrrolidine-2-carbonitrile 

Relevant academic research and scientific papers

Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α

Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.

Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

Cycloaddition of furfurylamines to maleic anhydride and its substituted derivatives

The regio- and stereoselectivity of the [4+2] cycloaddition of maleic, citraconic, dichloromaleic, and dibromomaleic anhydrides to difurfuryl amines and secondary furfurylamines were studied. N-Furfuryl-, N-phenyl-, and N-benzylhexahydrooxoepoxyisoindole-7-carboxylic acids were synthesized. An approach was developed for obtaining hexahydroepoxyoxoisoindole-7-carboxylic acid unsubstituted at the nitrogen atom. Aromatization of the oxabicycloheptene fragment of the dihaloepoxyiso-indolonecarboxylic acids gave a series of 7-carboxy-2-R-isoindol-1-ones.

Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells

Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.

A facile, protic ionic liquid route to N-substituted 5-hydroxy-4-methyl-3- oxoisoindoline-1-carboxamides and N-substituted 3-oxoisoindoline-4-carboxylic acids

Treatment of highly decorated bicyclo[2.2.1]heptadienes with the protic ionic liquid, TfOH:TEA effected quantitative conversion to the corresponding N-substituted 5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamides. This approach provides rapid access important chemical space for the rapid development of highly functionalised oxoisoindoline and is highly substrate tolerant.

Synthesis of phosphonic acids possessing isoindolin-1-one moiety: Unexpected acid-catalyzed c-p-bond cleavage

Phosphonic acids bearing isoindolin-1-one moiety were synthesized by dehydrative aromatization of the corresponding epoxyisoindolyl phosphonates. A mechanism for the unexpected acid catalyzed dephosphorylation was proposed.

Synthesis of advanced intermediates of lennoxamine analogues

A simple and convenient method for synthesis of advanced isoindolone intermediates of lennoxamine and analogues is described in this paper. The intramolecular Diels-Alder reaction of furan is used as a key step in this synthesis. Georg Thieme Verlag Stuttgart.

Preparative synthesis of 7-carboxy-2-R-isoindol-1-ones

A preparative method for the synthesis of 7-carboxy-2-R-isoindol-1-ones was developed on the basis of the [4+2] cycloaddition of secondary furfurylamines to maleic anhydride.