- Discovery of decamidine as a new and potent PRMT1 inhibitor
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Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (2j), which possesses the longest linker in the series, displayed 2- and 4-fold increase in PRMT1 inhibition (IC50 = 13 μM), compared with furamidine and stilbamidine. The inhibitory activity toward PRMT1 was validated by secondary orthogonal assays. Docking studies showed that the increased activity is due to the extra interaction of the amidine group with the SAM binding pocket, which is absent when the linker is not long enough. These results provide structural insights into developing the amidine type of PRMT1 inhibitors.
- Zhang, Jing,Qian, Kun,Yan, Chunli,He, Maomao,Jassim, Brenson A.,Ivanov, Ivaylo,Zheng, Yujun George
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p. 440 - 444
(2017/03/08)
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- Hexanoic the trunk decides method for the synthesis of
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The invention discloses a synthetic method of hexamidine. Hexamidine is a key raw material for producing antibiotic medicines hexamidine salts (such as dihydrochloride and dihydroxyethyl sulfonate). The synthetic method of hexamidine comprises the following steps: 1, reacting p-cyanophenol with 1,6-dibromohexane in an ethanol-water solution of sodium hydroxide to prepare 1,6-(p-cyanophenyl)hexyl diether (an intermediate I); 2, carrying out alcoholysis on the intermediate I in ethanol-toluene under the catalysis of trifluoroacetic acid or methanesulfonic acid to prepare 1,6-(p-ethyl iminoformate phenyl)hexyl diether (an intermediate II); and 3, carrying out aminolysis on the intermediate II in a methanol-ammonia solution to prepare hexamidine. The total yield of three-step synthesis is greater than 72%, and a nuclear magnetism identification result shows that the above obtained product is a preconceived structure product. The method is suitable for large-scale industrial production.
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Paragraph 0024; 0062; 0063; 0064
(2016/11/28)
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- Preparing method for efficient hexamidine dihydroxyethyl sulfonate
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The invention relates to a preparing method for efficient hexamidine dihydroxyethyl sulfonate. The preparing method is characterized by including the following steps that 1, sodium hydroxide and water are added into an ethanol solution of 4-cyanophenol, after reflux is carried out for 1 h, 1,6-dibromohexane is added, the mixture reacts for 3 h, and the product is filtered and dried to obtain 4,4'-dicyano-1,6-diphenoxy hexane; 2, anhydrous HCl gas is introduced into the product obtained in the previous step and reacts for 72 h at the temperature of 25 DEG C after gas introduction is completed, the product is filtered and dried to obtain 4,4'-imino ethyl ester-1,6-diphenoxy hexane; 3, dry ammonia gas is introduced into the product obtained in the previous step, reaction is carried out at controlled temperature for 15 h, then heating reflux is carried out for 9 h, isethionic acid is added, and a residue is heated to be dissolved, filtered in a suction mode while hot and dried to obtain hexamidine dihydroxyethyl sulfonate. It is found that the reaction has the advantages of being mild in condition, high in conversion rate and short in reaction time and has higher industrialized application value compared with prior synthesis methods.
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Paragraph 0037; 0040; 0041
(2018/02/04)
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- Small Molecule Inhibitors of Ca2+-S100B Reveal Two Protein Conformations
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The drug pentamidine inhibits calcium-dependent complex formation with p53 (CaS100B·p53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of CaS100B·inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the "FF-gate". For symmetric pentamidine analogues (CaS100B·5a, CaS100B·6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue (CaS100B·17), this same channel was open. The CaS100B·17 structure illustrates, for the first time, a pentamidine analog capable of binding the "open" form of the "FF-gate" and provides a means to block all three "hot spots" on CaS100B, which will impact next generation CaS100B·p53 inhibitor design.
- Cavalier, Michael C.,Ansari, Mohd. Imran,Pierce, Adam D.,Wilder, Paul T.,McKnight, Laura E.,Raman, E. Prabhu,Neau, David B.,Bezawada, Padmavani,Alasady, Milad J.,Charpentier, Thomas H.,Varney, Kristen M.,Toth, Eric A.,MacKerell, Alexander D.,Coop, Andrew,Weber, David J.
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p. 592 - 608
(2016/02/09)
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- Analogues of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment of experimental Pneumocystis carinii pneumonia
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A series of 33 analogues of the anti-Pneumocystis carinii drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) was synthesized for screening against a rat model of P. carinii pneumonia (PCP). Twenty-five of the compounds showed efficacy against PCP when compared to a saline-treated control group. Two compounds, 1,4-bis(4-amidinophenoxy)butane (butamidine, 6) and 1,3-bis(4-amidino-2-methoxyphenoxy)propane (DAMP, 16), were statistically more effective than the parent drug in treating PCP in the rat model of infection. In addition to their activity against PCP, the compounds were also evaluated for antitrypsin activity, ability to inhibit thymidylate synthetase, affinity for DNA, and toxicity. No correlation was observed between the tested molecular interactions of the diamidines and their effectiveness against PCP.
- Tidwell,Jones,Geratz,Ohemeng,Cory,Hall
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p. 1252 - 1257
(2007/10/02)
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