Shobanbabu Bommagani1, Jessica Ponder2, Narsimha R Penthala1, Venumadhav Janganati1, Craig T Jordan2, Michael J Borrelli3, Peter A Crooks4. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. 2. Division of Hematology, University of Colorado, Aurora, CO 80045, USA. 3. Department of Radiology and Neurology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
Abstract
A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03-0.30 μM and 0.04-0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05-0.40 μM and 0.04-0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01-0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SF gliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1 AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33-1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpene MMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors.
A series of novel, class="Chemical">heteroaryl carboxylic acid conjugates of the n class="Chemical">sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 humanhematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03-0.30 μM and 0.04-0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05-0.40 μM and 0.04-0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01-0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SFgliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33-1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpeneMMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors.
Authors: Monica L Guzman; Randall M Rossi; Lilliana Karnischky; Xiaojie Li; Derick R Peterson; Dianna S Howard; Craig T Jordan Journal: Blood Date: 2005-02-01 Impact factor: 22.113
Authors: Yun Dai; Monica L Guzman; Shuang Chen; Li Wang; Sin-Kei Yeung; Xin-Yan Pei; Paul Dent; Craig T Jordan; Steven Grant Journal: Br J Haematol Date: 2010-08-02 Impact factor: 6.998
Authors: L V Rubinstein; R H Shoemaker; K D Paull; R M Simon; S Tosini; P Skehan; D A Scudiero; A Monks; M R Boyd Journal: J Natl Cancer Inst Date: 1990-07-04 Impact factor: 13.506
Authors: Monica L Guzman; Randall M Rossi; Sundar Neelakantan; Xiaojie Li; Cheryl A Corbett; Duane C Hassane; Michael W Becker; John M Bennett; Edmund Sullivan; Joshua L Lachowicz; Andrew Vaughan; Christopher J Sweeney; William Matthews; Martin Carroll; Jane L Liesveld; Peter A Crooks; Craig T Jordan Journal: Blood Date: 2007-09-05 Impact factor: 22.113
Authors: Shanshan Pei; Mohammad Minhajuddin; Kevin P Callahan; Marlene Balys; John M Ashton; Sarah J Neering; Eleni D Lagadinou; Cheryl Corbett; Haobin Ye; Jane L Liesveld; Kristen M O'Dwyer; Zheng Li; Lei Shi; Patricia Greninger; Jeffrey Settleman; Cyril Benes; Fred K Hagen; Joshua Munger; Peter A Crooks; Michael W Becker; Craig T Jordan Journal: J Biol Chem Date: 2013-10-02 Impact factor: 5.157
Authors: Venumadhav Janganati; Jessica Ponder; Meenakshisundaram Balasubramaniam; Poornima Bhat-Nakshatri; Eli E Bar; Harikrishna Nakshatri; Craig T Jordan; Peter A Crooks Journal: Eur J Med Chem Date: 2018-08-10 Impact factor: 6.514
Authors: Emilie Darrigues; Edward H Zhao; Annick De Loose; Madison P Lee; Michael J Borrelli; Robert L Eoff; Deni S Galileo; Narsimha R Penthala; Peter A Crooks; Analiz Rodriguez Journal: Int J Mol Sci Date: 2021-10-03 Impact factor: 5.923
Authors: Amirtham J A Ranjitsingh; Sandhanasamy Devanesan; Mohamad S AlSalhi; Parameswari Paul; C Padmalatha Journal: J King Saud Univ Sci Date: 2021-11-12