1164548-54-2Relevant academic research and scientific papers
Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing
Chen, Jonathan L.,Zhang, Peiyuan,Abe, Masahito,Aikawa, Haruo,Zhang, Liying,Frank, Alexander J.,Zembryski, Timothy,Hubbs, Christopher,Park, Hajeung,Withka, Jane,Steppan, Claire,Rogers, Lucy,Cabral, Shawn,Pettersson, Martin,Wager, Travis T.,Fountain, Matthew A.,Rumbaugh, Gavin,Childs-Disney, Jessica L.,Disney, Matthew D.
, p. 8706 - 8727 (2020)
Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.
PYRROLOPYRIMIDINE DERIVATIVES AS MODULATORS OF MULTI-DRUG RESISTANCE (MDR)
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Page 35, (2010/02/10)
A compound which is a pyrrolopyrimidine of formula (I) wherein R1 is selected from H, Cl-C6 alkyl which is unsubstituted or substituted, (CH2)nAr1, (CH2)pNR4R5, halogen and (CH2)pX; R2 is CH2)pArl; R3 is selected from H, Cl -C6 alkyl which is unsubstituted or substituted, (CH2)pZ and (CH2)pArl; P is an unsaturated 5, 6, or 7 membered carbocyclic or heterocyclic ring which is unsubstituted or substituted; R4 and R5 which are the same or different are selected from H, Cl -C6 alkyl which is unsubstituted or substituted, (CH2)nC3-C10 cycloalkyl, (CH2)nAr1 , and (CH2)nOR6, or R4 and R5 together with the nitrogen atom to which they are attached, form a saturated five or six membered nitrogen containing heterocyclic ring which may contain one extra heteroatom selected from 0, N and S and which is unsubstituted or substituted; R6 is selected from H, Cl -C6 alkyl which is unsubstituted or substituted, C3-C10 cycloalkyl, (CH2)nOC1-C6alkyl which is unsubstituted or substituted, (CH2)nO(CH2)nAr1 , (CH2)nCO2C1-C6,alkyl which is unsubstituted or substituted and (CH2)nAr1; X is selected from CN, azide, (CH2)nNHSO2R6 and (CH2)nNHCOR6; Z is selected from CN, CO2R6 and CONR4R5; Ar1 is the same or different when more than one is present within a given substituent group and is an unsaturated C6-C10 membered carbocylic group or an unsaturated 5-11 membered heterocycle, either of which is unsubstituted or substituted; p is an integer of 1 to 6; n is the same or different when more than one is present within a given substituent group and is 0 or an integer of 1 to 6; with the proviso that the pyrrolepyrimidine compound of formula (I) is other than 1-(4-benzyl-piperazin-1-yl)-9H-2,4,9-triaza-fluorene; and the pharmaceutically acceptable salts thereof, have activity as inhibitors of MRP (multidrug resistant protein) and may thus be used to modulate multidrug resistance, for instance in potentiating the cytotoxicity of a chemotherapeutic agent.
SYNTHESIS OF N-(INDOL-3-YL)-N',N'-DIALKYLAMIDINES BY THE VILSMEIER REACTION WITH 3-AMINOINDOLES
Simakov, S. V.,Velezheva, V. S.,Kozik, T. A.,Suvorov, N. N.
, p. 61 - 65 (2007/10/02)
3-Aminoindoles substituted at C-2 and C-5 of the indole ring are converted by the action of Vilsmeier complexes into N-(indol-3-yl)-N',N'-dialkylamidines.When C-2 is unsubstituted, the formylation proceeds but not the acetylation of this position.N-(Indol-3-yl)-N',N'-dimethylacetamidine reacts with the complex obtained from DMF and POCl3 to give 2-dimethylamino-3-formyl-δ-carboline.The optimal conditions were found for the conversion of amidines to amides.
