An activated equivalent of lactide toward organocatalytic ring-opening polymerization

International audienc

Preparation of N-carbacycle monosubstituted indolocarbazoles for therapeutic use as protein kinase inhibitors

N-(carbacyclyl)-indolocarbazoles, such as I [R = substituted or unsubstituted 5 or 6 membered carbacyclyl; R3, R4 = H, halogen, alkyl, carboxy, carboxamide, amino, alkoxy, etc.], were prepd. as protein kinase inhibitors which are useful for the treatment of non-insulin dependent diabetes mellitus, acute stroke and other neurotraumatic injuries, malignant diseases, and neurodegenerative diseases, such as Alzheimer's disease. Thus, NAD 006 (II) was prepd. via a multistep synthetic sequence starting from cyclopentadiene, 1H-indole-3-acetonitrile and 2-indolone. The prepd. staurosporine analogs were assayed for inhibition of extracellular signal regulated kinase 2, protein kinase A, protein kinase C and glycogen synthase kinase 3\u3b2

Preparation of N,N-bridged, nitrogen-substituted carbacyclic indolocarbazoles for use in pharmaceutical compositions as protein kinase inhibitors

This invention relates to the prepn. of novel carbacyclic indolocarbazoles, such as I [R1 = NR13R14; R2 = H, CN, alkyl, aryl, heteroaryl, acyl, carboxy, carboxamido; R1R2 = spiro nitrogen contg. heterocycle, such as spirohydantoyl; R3 = H, OR13, OCOR13, OCONHR13, OCONR13R14; R1R3 = fused heterocycle, such as -OSO2O-, and R2 = H; R4, R6 = H, CN, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, carboxy. carboxamido, etc.; R8R9, R10R11 = H2, O, S; R8 = H, R9 = OH; R10 = H, R11 = OH; R12 = H, alkyl, cycloalkyl, benzyl aryl heteroaryl, acyl, carboxy, etc.; R13, R14 = H, alkyl, cycloalkyl, acyl, aryl, etc.], for therapeutic use as protein kinase inhibitors with advantageous pharmaceutical properties. These indolocarbazoles are claimed for use in the treatment of CNS diseases, non-insulin-dependent diabetes mellitus, acute stroke and other neuro-traumatic injuries, diabetes mellitus, malignant diseases, diseases caused by malfunctioning of specific signaling pathways and neurodegenerative diseases, such as Alzheimer's disease. Thus, indolocarbazole II (R1 = \u3b2-NH2, R2 = \u3b1-H, R3 = H) was prepd. starting from cyclopentadiene, 4-methoxybenzyl amine, dichloromaleic anhydride, and indole via a multistep synthetic sequence which included a reaction of 12,13-dihydro-6-[(4-methoxyphenyl)methyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione with cis-3,5-dibromocyclopentene using NaH in THF to form II (R1R3 = bond, R2 = H) in 90.4% yield. II (R1R3 = bond, R2 = H), which contains the target ring skeleton, further underwent an hydroxylation sequence using BH2.THF followed by NaOH and H2O2 to form alc. II (R1 = \u3b1-OH, R2 = \u3b2-H, R3 = H), oxidn. of the alc. to the corresponding ketone II (R1R2 = O, R3 = H), reaction of the ketone with benzylamine to give N-benzyl amine II (R1 = \u3b2-NHCH2Ph, R2 = \u3b1-H, R3 = H) and, finally, N-debenzylation to give the desired indolocarbazole II (R1 = \u3b2-NH2, R2 = \u3b1-H, R3 = H). The prepd. indolocarbazoles were assayed for inhibiting the activity of a group of protein kinases consisting of extracellular signal regulated kinase 2 (ERK2), protein kinase A (PKA), protein kinase C (PKC) and glycogen synthase kinase 3\u3b2 (GSK3\u3b2)

Bare histidine-serine models : implications and impact of hydrogen bonding on nucleophilicity

International audienceA new family of 2-hydroxyalk(en/yn)ylimidazoles has been evaluated as serine–histidine bare dyad models for the ring-opening reaction of L-lacOCA, a cyclic O-carboxyanhydride. These models were selected to unravel the implication of intramolecular hydrogen bonding and to substantiate its influence on the nucleophilicity of the alcohol moiety, as it is suspected to occur in enzyme active sites. Although designed to exclusively facilitate the preliminary step of proton transfer during the studied ring-opening reaction, these minimalistic models depicted a measureable increase in reactivity relative to the isolated fragments. A couple of reliable experimental and theoretical methods have been developed to readily monitor the strength of the intramolecular hydrogen bond in dilute solution. Results show that the folded conformers are the most nucleophilic species because of the intramolecular hydrogen bond