Lead Optimization of 2-Cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides for Targeting the HER-2 Overexpressed Breast Cancer Cell Line SKBr-3

被引:11
作者
Bhat, Mashooq A. [1 ]
Al-Dhfyan, Abdullah [2 ,3 ]
Naglah, Ahmed M. [4 ,5 ]
Khan, Azmat Ali [1 ]
Al-Omar, Mohamed A. [4 ]
机构
[1] King Saud Univ, Dept Pharmaceut Chem, Coll Pharm, Riyadh 11451, Saudi Arabia
[2] King Faisal Specialized Hosp & Res Ctr, Stem Cell & Tissue Reengn Program, Riyadh 11211, Saudi Arabia
[3] King Saud Univ, Dept Pharmacol & Toxicol, Coll Pharm, Riyadh 11451, Saudi Arabia
[4] King Saud Univ, Dept Pharmaceut Chem, Coll Pharm, Drug Explorat & Dev Chair, Riyadh 11451, Saudi Arabia
[5] Natl Res Ctr, Chem Ind Res Div, Peptide Chem Dept, Cairo 12622, Egypt
来源
MOLECULES | 2015年 / 20卷 / 10期
关键词
thiosemicarbazones; HER-2; SKBr-3; cells; BT-474; cancer stem cells; STEM-CELLS; IDENTIFICATION; RESISTANCE; INHIBITORS; CARCINOMA; MARKER;
D O I
10.3390/molecules201018246
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lead derivatives of 2-cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides 1-18 were synthesized, characterized and evaluated in vitro against HER-2 overexpressed breast cancer cell line SKBr-3. All the compounds showed activity against HER-2 overexpressed SKBr-3 cells with IC50 = 17.44 +/- 0.01 mu M to 53.29 +/- 0.33 mu M. (2Z)-2-(3-Hydroxybenzylidene)-N-(3-methoxyphenyl)hydrazinecarbothioamide (12, IC50 = 17.44 +/- 0.01 mu M) was found to be most potent compound of this series targeting HER-2 overexpressed breast cancer cells compared to the standard drug 5-fluorouracil (5-FU) (IC50 = 38.58 +/- 0.04 mu M). Compound 12 inhibited the cellular proliferation via DNA degradation.
引用
收藏
页码:18246 / 18263
页数:18
相关论文
共 25 条
[1]   Prospective identification of tumorigenic breast cancer cells [J].
Al-Hajj, M ;
Wicha, MS ;
Benito-Hernandez, A ;
Morrison, SJ ;
Clarke, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (07) :3983-3988
[2]   Targeting HER-2 over expressed breast cancer cells with 2-cyclohexyl-N-[(Z)-(substituted phenyl/furan-2-yl/thiophene-2-yl)methylidene]hydrazinecarbothioamide [J].
Bhat, Mashooq Ahmad ;
Al-Dhfyan, Abdullah ;
Khan, Azmat Ali ;
Al-Harbi, Nouf ;
Manogaran, P. S. ;
Alanazi, Amer M. ;
Fun, Hoong-Kun ;
Al-Omar, Mohamed A. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2015, 25 (01) :83-87
[3]   Understanding the cancer stem cell [J].
Bomken, S. ;
Fiser, K. ;
Heidenreich, O. ;
Vormoor, J. .
BRITISH JOURNAL OF CANCER, 2010, 103 (04) :439-445
[4]   Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell [J].
Bonnet, D ;
Dick, JE .
NATURE MEDICINE, 1997, 3 (07) :730-737
[5]   Aldehyde Dehydrogenase 1-Positive Cancer Stem Cells Mediate Metastasis and Poor Clinical Outcome in Inflammatory Breast Cancer [J].
Charafe-Jauffret, Emmanuelle ;
Ginestier, Christophe ;
Iovino, Flora ;
Tarpin, Carole ;
Diebel, Mark ;
Esterni, Benjamin ;
Houvenaeghel, Gilles ;
Extra, Jean-Marc ;
Bertucci, Francois ;
Jacquemier, Jocelyne ;
Xerri, Luc ;
Dontu, Gabriela ;
Stassi, Giorgio ;
Xiao, Yi ;
Barsky, Sanford H. ;
Birnbaum, Daniel ;
Viens, Patrice ;
Wicha, Max S. .
CLINICAL CANCER RESEARCH, 2010, 16 (01) :45-55
[6]   Colorectal carcinoma: Diagnostic, prognostic, and molecular features [J].
Compton, CC .
MODERN PATHOLOGY, 2003, 16 (04) :376-388
[7]   Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity [J].
Dilovic, Ivica ;
Rubcic, Mirta ;
Vrdoljak, Visnja ;
Pavelic, Sandra Kraljevic ;
Kralj, Marijeta ;
Piantanida, Ivo ;
Cindric, Marina .
BIOORGANIC & MEDICINAL CHEMISTRY, 2008, 16 (09) :5189-5198
[8]   Triapine (3-aminopyridine-2-carboxaldehydethiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity [J].
Finch, RA ;
Liu, MC ;
Grill, SP ;
Rose, WC ;
Loomis, R ;
Vasquez, KM ;
Cheng, YC ;
Sartorelli, AC .
BIOCHEMICAL PHARMACOLOGY, 2000, 59 (08) :983-991
[9]   ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome [J].
Ginestier, Christophe ;
Hur, Min Hee ;
Charafe-Jauffret, Emmanuelle ;
Monville, Florence ;
Dutcher, Julie ;
Brown, Marty ;
Jacquemier, Jocelyne ;
Viens, Patrice ;
Kleer, Celina G. ;
Liu, Suling ;
Schott, Anne ;
Hayes, Dan ;
Birnbaum, Daniel ;
Wicha, Max S. ;
Dontu, Gabriela .
CELL STEM CELL, 2007, 1 (05) :555-567
[10]   Synthesis and structure-activity relationships of parasiticidal thiosemicarbazone cysteine protease inhibitors against Plasmodium falciparum, Trypanosoma brucei, and Trypanosoma cruzi [J].
Greenbaum, DC ;
Mackey, Z ;
Hansell, E ;
Doyle, P ;
Gut, J ;
Caffrey, CR ;
Lehrman, J ;
Rosenthal, PJ ;
McKerrow, JH ;
Chibale, K .
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (12) :3212-3219