TY - JOUR
T1 - Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe
AU - Jouanneau, Morgan
AU - McClary, Brandon
AU - Reyes, Jeremy Chris P.
AU - Chen, Rong
AU - Chen, Yuling
AU - Plunkett, William
AU - Cheng, Xin
AU - Milinichik, Andrew Z.
AU - Albone, Earl F.
AU - Liu, Jun O.
AU - Romo, Daniel
N1 - Funding Information:
We are grateful for financial support from NIH ( R37 GM052964 ) to D.R., the Welch Foundation ( AA-1280 ) to D.R., the Flight Attendant Medical Research Institute to J.O.L., and a NRSA ( 5F31AT008324-02 ) fellowship from NIH to B.M. Some of this work was performed at Texas A&M University, Department of Chemistry. Investigations using primary CLL cells were supported by the CLL Global Research Foundation (IP13086447) to W.P. We thank Dr. Howard Williams (Texas A&M University) for NMR assistance and Dr. William G. Wierda (Univ. TX MD Anderson Cancer Center) for providing the primary human CLL cells.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - (-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.
AB - (-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.
KW - Agelastatin A
KW - Diazirine
KW - Photoaffinity probe
KW - Pyrrole-aminoimidazole alkaloid
KW - Structure-activity relationship
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U2 - 10.1016/j.bmcl.2016.02.051
DO - 10.1016/j.bmcl.2016.02.051
M3 - Article
C2 - 26951751
AN - SCOPUS:84959459130
SN - 0960-894X
VL - 26
SP - 2092
EP - 2097
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 8
ER -