68682-28-0Relevant academic research and scientific papers
The antimalarial drug mefloquine enhances TP53 premature termination codon readthrough by aminoglycoside G418
Ferguson, Michael W.,Gerak, Chloe A.N.,Chow, Christalle C.T.,Rastelli, Ettore J.,Elmore, Kyle E.,Stahl, Florian,Hosseini-Farahabadi, Sara,Baradaran-Heravi, Alireza,Coltart, Don M.,Roberge, Michel
, (2019/07/02)
Nonsense mutations constitute ~10% of TP53 mutations in cancer. They introduce a premature termination codon that gives rise to truncated p53 protein with impaired function. The aminoglycoside G418 can induce TP53 premature termination codon readthrough and thus increase cellular levels of full-length protein. Small molecule phthalimide derivatives that can enhance the readthrough activity of G418 have also been described. To determine whether readthrough enhancers exist among drugs that are already approved for use in humans, we tested seven antimalarial drugs for readthrough of the common R213X TP53 nonsense mutation in HDQ-P1 breast cancer cells. Mefloquine induced no TP53 readthrough activity as a single agent but it strongly potentiated readthrough by G418. The two enantiomers composing pharmaceutical mefloquine potentiated readthrough to similar levels in HDQ-P1 cells and also in SW900, NCI-H1688 and HCC1937 cancer cells with different TP53 nonsense mutations. Exposure to G418 and mefloquine increased p53 phosphorylation at Ser15 and P21 transcript levels following DNA damage, indicating p53 produced via readthrough was functional. Mefloquine does not appear to enhance readthrough via lysosomotropic effects as it did not significantly affect lysosomal pH, the cellular levels of G418 or its distribution in organellar or cytosolic fractions. The availability of a readthrough enhancer that is already approved for use in humans should facilitate study of the therapeutic potential of TP53 readthrough in preclinical cancer models.
Asymmetric Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride
Rastelli, Ettore J.,Coltart, Don M.
, p. 9567 - 9575 (2016/11/02)
The asymmetric (er > 99:1) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The Sharpless asymmetric dihydroxylation is the key asymmetric transformation used in the synthesis of this intermediate. It is carried out on an olefin that is accessed in three steps from commercially available materials, making the overall synthetic sequence very concise. The common diol intermediate derived from the Sharpless asymmetric dihydroxylation is converted into either a trans- or cis-epoxide, and these are subsequently converted to (+)-anti- and (-)-syn-mefloquine, respectively. X-ray crystallographic analysis of derivatives of (+)-anti- and (-)-syn-mefloquine is used to lay to rest a 40 year argument regarding the absolute stereochemistry of the mefloquines. A formal asymmetric (er > 99:1) synthesis of (+)-anti-mefloquine hydrochloride is also presented that uses a Sharpless asymmetric epoxidation as a key step.
A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines
Rastelli, Ettore J.,Coltart, Don M.
, p. 14070 - 14074 (2016/01/25)
A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+)-mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine.
A stereospecific synthesis and unambiguous assignment of the absolute configuration of (-)-erythro-Mefloquine hydrochloride
Zhou, Gang,Liu, Xian,Liu, Xueying,Nie, Huifang,Zhang, Shengyong,Chen, Weiping
supporting information, p. 3575 - 3580 (2014/01/06)
(-)-erythro-Mefloquine hydrochloride was synthesized stereospecifically from commercially available (S)-(-)-1-Boc-2-piperidinecarboxylic acid in four steps without disturbing the chiral center, and the absolute configuration of (-)-erythro-mefloquine hydrochloride was unambiguously determined as (11R,12S). (11S,12R)-(+)-erythro-Mefloquine hydrochloride was synthesized utilizing [(S,S)-TsDpen]Ru(p-cymene)Cl complexes-catalyzed enantioselective transfer hydrogenation of pyridyl ketone 7 as the key step, and the sense of asymmetric induction of 2-pyridyl ketone 7 is opposite to that of normal ketones in the transfer hydrogenation. Our results confirm the correctness of the determination of the absolute configuration by three physical chemistry methods, and, unbelievably, the erroneous assignments by all previous five asymmetric syntheses. Copyright
Concise synthesis and antimalarial activity of all four mefloquine stereoisomers using a highly enantioselective catalytic borylative alkene isomerization
Ding, Jinyue,Hall, Dennis G.
, p. 8069 - 8073 (2013/08/23)
The pluses and minuses of mefloquine: A highly enantioselective catalytic borylative isomerization/aldehyde allylboration method for the stereoselective synthesis of the antimalarial drug mefloquine was optimized, thus leading to an efficient synthesis of all four mefloquine stereoisomers and analogues (see scheme). The absolute configuration of these potent compounds was determined for the first time by using chemical synthesis. Copyright
Practical asymmetric synthesis of (+)-erythro mefloquine hydrochloride
Hems, William P.,Jackson, William P.,Nightingale, Peter,Bryant, Rob
experimental part, p. 461 - 463 (2012/08/08)
A highly enantioselective and cost efficient process for the synthesis of (+)-erythro mefloquine has been developed. The key step is an enantioselective reduction of pyridyl ketone KI using transfer hydrogenation with formic acid as the hydrogen source. T
Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones
Knight, John D.,Sauer, Scott J.,Coltart, Don M.
supporting information; experimental part, p. 3118 - 3121 (2011/08/03)
Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.
CRYSTALLINE FORMS OF (+)- AND (-)-ERYTHRO-MEFLOQUINE HYDROCHLORIDE
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Page/Page column 19-20, (2008/06/13)
(+)- or (-)-erythro-Mefloquine hydrochloride can exist in four crystalline forms A, B, C and D, whereby form A is the most stable form. Form A can be directly produced in morphological forms like thick columns, cuboids, cubes and cube-like forms, which can be easily handled during processing and formulation. (+)- or (-)-eroryth-Mefloquine hydrochloride also forms solvates with acetone, methyl ethyl ketone and tetrahydrofuran.
