Synthesis and Evaluation of (2-(4-Methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (NSC23925) Isomers To Reverse Multidrug Resistance in Cancer

Duan, Zhenfeng; Li, Xin; Huang, Haoxi; Yuan, Wei; Zheng, Shao‐Liang; Liu, Xianzhe; Zhang, Zhan; Choy, Edwin; Harmon, David C.; Mankin, Henry J.; Hornicek, Francis J.

doi:10.1021/jm300117u

Cited by 44 publications

(37 citation statements)

References 17 publications

(53 reference statements)

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“…Results for the analogs are summarized in Table S1. The vacquinol class of compounds, 2-piperidinyl-4-quinolinemethanols, were originally developed as antimalarials (81,82), and in addition to their activity against M. tuberculosis and brain cancer cells, they can inhibit efflux pumps and are of interest in combating multidrug resistance in cancer cells (79,83,84), suggesting the possibility that their uncoupling effects could contribute to a diverse range of activities. The fact that vacquinol also has promising in vivo activity against GBM, a good in vivo pharmacokinetic profile, oral bioavailability, and favorable overall preclinical characteristics (80), in addition to killing M. tuberculosis, makes it an interesting lead for antiinfective development.…”

Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

169

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There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

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Section: Resultsmentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

148

169

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“…Western blotting analysis was performed as previously described [14,19]. Protein lysates were harvested from osteosarcoma cells by using 1×RIPA Lysis Buffer (Upstate Biotechnology, Charlottesville, VA, USA), and the concentrations were determined using Protein Assay Reagent (Bio-Rad Laboratories, Hercules, CA, USA) and a spectrophotometer (Beckman DU-640, Beckman Instruments, Inc., Columbia, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

Shen

Choy

et al. 2015

Cancer Chemother Pharmacol

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Purpose Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22% of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild type p53 can increase chemosensitivity in MDR osteosarcoma cells. Methods We transfected a plasmid encoding the wild type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities. Results Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53 induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly. Conclusions These results demonstrated that tansfection of wild type p53 increases chemosensitivity through inhibiting either IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines.

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“…[19][20][21] Although major advances have been made by researchers but the medical need is still largely unmet due to many factors; among which are the lack of selectivity of conventional drugs leading to toxicity, the metastatic spreading, and multi -drug resistance. [22][23][24][25][26][27] Novel and selective anticancer agents are urgently required due to problems associated with currently available anticancer drugs. The plant Euclea natalensis (A.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines

Kishore

Binneman

Mahapatra

et al. 2014

Bioorganic & Medicinal Chemistry

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In an effort to establish new candidates with enhanced anticancer activity of 5-hydroxy-7-methyl-1,4-naphthoquinone scaffold (7-methyljuglone) previously isolated from the root extract of Euclea natalensis, a series of 7-methyljuglone derivatives have been synthesized and assessed for cytotoxicity on selected human cancer lines. These compounds were screened in vitro for anticancer activity on MCF-7, HeLa, SNO and DU145 human cancer cell lines by MTT assay. Most of them exhibited significant toxicity on cancer cell lines with lower IC 50 values. The most potent derivative (19) exhibited the toxicity on HeLa and DU145 cell lines with IC 50 value of 5.3 and 6.8 µM followed by compound (5) with IC 50 value of 10.1 and 9.3 µM, respectively. Structureactivity relationship reveals that the fluoro substituents at position C-8 while hydroxyl substituents at C-2 and C-5 positions played an important role in toxicity.

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Synthesis and Evaluation of (2-(4-Methoxyphenyl)-4-quinolinyl)(2-piperidinyl)methanol (NSC23925) Isomers To Reverse Multidrug Resistance in Cancer

Cited by 44 publications

References 17 publications

Antiinfectives targeting enzymes and the proton motive force

Antiinfectives targeting enzymes and the proton motive force

p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines

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