title: Structure-Activity Relationship Study of Rakicidins: Overcoming Chronic Myeloid Leukemia Resistance to Imatinib with 4-Methylester-Rakicidin A.
abstract: Natural product rakicidin A induces cell death in TKI-resistant chronic myelogenous leukemia (CML) cells. Therefore, 14 rakicidin A analogues were synthesized via a highly efficient combinatorial strategy and were evaluated against CML cell lines. The conjugated diene moiety was found to be crucial for the anti-CML activity of rakicidin A, and the changes in the configuration(s) at C-2, C-3, C-14, C-15, and C-16 resulted in lower levels of anti-CML activity. The most promising compound was 4-methylester rakicidin A (1a). Compared with rakicidin A, 1a exhibited 2.8-fold greater potency against the imatinib-resistant cell line K562/G(+) and approximately 100-fold enhanced potency compared with that of imatinib. Furthermore, compound 1a demonstrated a significantly lower resistance index against Ba/F3 cells expressing BCR-ABL(T315I) than bosutinib, dasatinib, nilotinib, and ponatinib, while 1a exhibited less effect on normal hematopoietic cells. Preliminary results indicated that 1a down-regulated caspase-3 and PARP, which contributes to its K562 cell inhibitory activity.
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.|School of Life Sciences, Shandong University of Technology , Zibo 255049, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Sang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Ding
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Jinghan
authors.initials: J
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Bingxia
authors.initials: B
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Jianlei
authors.initials: J
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.|High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science , 190 Kai Yuan Avenue, Guangzhou 510530, People's Republic of China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science , 190 Kai Yuan Avenue, Guangzhou 510530, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.|High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Liu
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine , Tianjin 300457, People's Republic of China.
authors.forename: Cuigai
authors.initials: C
authors.lastname: Bai
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University , Tianjin 300071, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D055666:Lipopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D047630:Depsipeptides
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D055666:Lipopeptides; D010456:Peptides, Cyclic; C000723972:rakicidins; D047630:Depsipeptides