TY - JOUR
T1 - Sterically induced conformational restriction
T2 - Discovery and preclinical evaluation of novel pyrrolo[3,2-d]pyrimidines as microtubule targeting agents
AU - Pavana, Roheeth Kumar
AU - Shah, Khushbu
AU - Gentile, Taylor
AU - Dybdal-Hargreaves, Nicholas F.
AU - Risinger, April L.
AU - Mooberry, Susan L.
AU - Hamel, Ernest
AU - Gangjee, Aleem
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/11/1
Y1 - 2018/11/1
N2 - The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem. 2018, 61, 1704–1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.
AB - The discovery, synthesis and biological evaluations of a series of nine N5-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds with microtubule depolymerizing activity were identified. Some of these compounds also circumvent clinically relevant drug resistance mechanisms (expression of P-glycoprotein and βIII tubulin). Compounds 4, 5, and 8–13 were one to two-digit nanomolar (IC50) inhibitors of cancer cells in culture. Contrary to recent reports (Banerjee et al. J. Med. Chem. 2018, 61, 1704–1718), the conformation of the most active compounds determined by 1H NMR and molecular modeling are similar to that reported previously and in keeping with recently reported X-ray crystal structures. Compound 11, freely water soluble as the HCl salt, afforded statistically significant inhibition of tumor growth in three xenograft models [MDA-MB-435, MDA-MB-231 and NCI/ADR-RES] compared with controls. Compound 11 did not display indications of animal toxicity and is currently slated for further preclinical development.
KW - Microtubule depolymerizers
KW - Microtubule targeting agents
KW - P-glycoprotein
KW - Preclinical agents
KW - Pyrrolo[3, 2-d]pyrimidines
KW - βIII tubulin
UR - http://www.scopus.com/inward/record.url?scp=85054543779&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054543779&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2018.09.025
DO - 10.1016/j.bmc.2018.09.025
M3 - Article
C2 - 30297118
AN - SCOPUS:85054543779
SN - 0968-0896
VL - 26
SP - 5470
EP - 5478
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 20
ER -