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Tuesday, August 25 • 4:00pm - 4:20pm
[0105] Teaching an old dog new tricks: chemical biology studies of pyrroloquinazolines

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7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. These include inhibition of dihydrofolate reductase (DHFR), protease-activated receptors (PAR) and protein tyrosine phosphatase 1B (PTP1B). However, the currently accessible chemical space derived from 1 is rather limited. In this presentation, we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1, N3 and N7, respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines were prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N3-acylated compounds were in general more potent than N1-acylated compounds while N7-acylation significantly reduced their solubility. Among the compounds evaluated, LBL1 possessed significantly more potent activity than 1 in MDA-MB-468 cells. More importantly, LBL1 was not toxic to normal human cells. Further chemical biology and mechanistic studies showed that LBL1 targets nuclear lamins to inhibit repair of double-strand DNA breaks (DSB) in breast cancer cells. The discovery of LBL1 as the first lamin-binding ligand from a focused novel library of 1 supports that 1 is a privileged scaffold. The availability of LBL1 should enable us to address the poorly understood molecular mechanisms of lamins in DSB repair processes

ST Lecturers
avatar for Xiangshu Xiao

Xiangshu Xiao

Associate Professor, Oregon Health & Science University
Associate Professor | Physiology and Pharmacology | Oregon Health & Science University  | 3181 SW Sam Jackson Park Rd  | Portland, OR  97239 



Tuesday August 25, 2015 4:00pm - 4:20pm
UCEN Lobero