?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F36688%2F&rft.title=DEVELOPMENT+OF+ANTIDOTES+FOR+ORGANOPHOSPHORUS+POISONING+AND+OF+ANTICANCER+SPLICING+REGULATORS&rft.creator=Bressin%2C+Robert&rft.description=Development+of+novel+small+molecules+with+application+in+medicine+and+chemical+biology+are+described+within.+One+of+the+two+projects+is+the+development+of+antidotes+for+organophosphorus+poisoning.+Current+therapy+for+organophosphorus+poisoning+uses+combination+treatment+that+relies+on+a+single+FDA-approved+molecule+in+its+class.+Poor+permeability+and+lack+of+broad-spectrum+efficiency+make+this+treatment+ineffective+against+most+organophosphorus+agents.+The+second+project+is+the+development+of+small+molecules+that+regulate+splicing.+Defects+in+the+splicing+machinery+and+aberrant+splicing+are+common+hallmarks+of+many+human+diseases%2C+including+cancer.+Small+molecules+that+regulate+splicing+can+correct+or+alter+gene+expression+to+treat+diseases.+There+are+currently+no+approved+therapies+that+target+the+human+spliceosome.%0D%0AThe+design+and+synthesis+of+pyridinium+oximes+as+antidotes+to+treat+organophosphorus+poisoning+is+presented.+Several+strategies+are+employed+to+mitigate+or+remove+the+positive+charge+to+produce+more+blood-brain+barrier+permeable+molecules+including+spirocyclization+and+resonance+delocalization.+The+reactivation+potential+of+these+compounds+against+organophosphorus+agent-inhibited+acetylcholinesterase+is+measured+in+vitro+against+a+panel+of+nerve+agents.+Initial+results+indicate+a+lead+compound+and+subsequent+structure-activity-relationship+studies+follow.+Preliminary+studies+in+mice+are+also+described.+The+lead+compound+from+this+study+has+been+demonstrated+to+have+broad-spectrum+efficiency+against+a+panel+of+nerve+agents%2C+however+the+permeability+was+not+improved.%0D%0ANext%2C+the+synthesis+of+analogs+of+FR901464%2C+a+natural+product+splicing+regulator%2C+is+discussed.+Meayamycin+B%2C+the+most+potent+analog%2C+has+been+previously+shown+to+have+low+picomolar+potency+against+various+cancer+cell+lines+and+regulate+the+alternative+splicing+of+the+myeloid+cell+leukemia+1+pre-mRNA.+We+describe+the+development+of+new+analogs+of+meayamycin+B+designed+to+improve+in+vivo+performance.+Two+structural+motifs+probed+in+this+study+are+the+4%E2%80%99-carbamate+and+the+1%E2%80%99-amide.+Growth+inhibition+against+several+cancer+cell+lines+are+measured.+The+new+analog+meayamycin+D+was+shown+to+inhibit+cancer+cell+growth+with+picomolar+potency+and+is+nearly+as+potent+as+meayamycin+B.&rft.date=2019-09-27&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F36688%2F1%2FRKB%2520ETD%2520Final.pdf&rft.identifier=++Bressin%2C+Robert++(2019)+DEVELOPMENT+OF+ANTIDOTES+FOR+ORGANOPHOSPHORUS+POISONING+AND+OF+ANTICANCER+SPLICING+REGULATORS.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++