Saquinavir mesylate的不对称合成研究进展

综述了治疗艾滋病药物Saquinavir mesylate的研究概况,对Saquinavir mesylate的不对称合成方法进行了归纳和总结,重点介绍了不对称还原、不对称醇醛缩合和Sharpless环氧化等反应在Saquinavir mesylate不对称合成中的应用。对今后Saquinavir mesylate不对称合成的研究动向进行了展望。     

平行-连续法合成沙奎那韦

采用平行-连续法合成了H IV蛋白酶抑制剂沙奎那韦。在中间体(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸的合成中,由喹哪啶-2-羧酸与亚硫酰氯反应得其酰氯作为活化剂,最佳反应条件为:回流8 h,收率95.0%;采用水介质合成了(S)-4-氨基-4-氧代-2-(喹啉-2-羧酰胺基)丁酸,收率82.0%。在硅胶存在下,(S)-1-〔(S)-2-环氧乙烷〕-2-苯基乙基氨基甲酸苄酯和(3S,4aS,8aS〕-N-叔丁基-十氢异喹啉-3-羧酰胺室温反应72 h,得(2S,3R)-4-〔(3S,4aS,8aS)-3-(叔丁氨甲酰基)-十氢异喹啉〕-3-羟基-1-苯基丁基-2-氨基甲酸苄酯,不经提纯,加入Pd/C〔w(Pd)=10%〕催化剂室温下与H2反应12 h脱去保护基,反应完毕后以乙腈重结晶即得另一中间体(3S,4aS,8aS)-2-〔(2R,3S)-3-氨基-2-羟基-4-苯基丁基〕-N-叔丁基-十氢异喹啉-3-羧酰胺,收率87.0%;两个中间体连接时,使用便宜、常见的N-羟基琥珀酰亚胺,收率82.0%。     

High-energy ball milling of saquinavir increases permeability across the buccal mucosa

Saquinavir (SQV), a candidate for buccal drug delivery, is limited by poor solubility. This study identified the effects of high-energy ball milling on the buccal permeability of SQV and compared it to the effects of chemical enhancers, i.e. ethylenediaminetetraacetic acid (EDTA), sodium lauryl sulfate (SLS), polyethylene glycol (PEG) and beta cyclodextrin (β-cyclodextrin). SQV was ball milled using a high energy planetary mill (1, 3, 15 and 30?h) and permeation studies across porcine buccal mucosa were performed using franz diffusion cells. Drug was quantified by UV spectrophotometry. Both unmilled and milled SQV samples were able to permeate the buccal mucosa. Milled samples of 15?h displayed the greatest flux of 10.40?±?1.24?µg/cm^2?h and an enhancement ratio of 2.61. All enhancers were able to increase the buccal permeability of unmilled SQV, with SLS achieving the greatest flux (6.99?±?0.7?µg/cm²) and an enhancement ratio of 1.75. However, all the milled SQV samples displayed greater permeability than SLS, the best chemical enhancer for unmilled SQV. Enhanced permeability by ball milling was attributed to reduction in particle size, formation of solid dispersions and an increase in solubility of milled samples. Microscopical evaluation revealed no significant loss in mucosal cellular integrity treated with either unmilled or milled SQV. Histological studies suggest that SQV uses both the paracellular and transcellular route of transport across the mucosa, with drug treatment having no permanent affects. High-energy ball milling was superior to the chemical enhancers studied for enhancement of SQV buccal permeation.     

Repurposing Alone and in Combination of the Antiviral Saquinavir with 5-Fluorouracil in Prostate and Lung Cancer Cells

Prostate and lung cancers are among the most common cancer types, and they still need more therapeutics. For this purpose, saquinavir (SAQ) was tested alone and in combination with 5-fluorouracil (5-FU). PC-3 and A549 cells were exposed to increasing concentrations of both drugs alone or in combination, with simultaneous or sequential administration. Cell viability was obtained using the MTT assay and synergism values using CompuSyn software. Results showed that SAQ was the more cytotoxic of both drugs in PC-3 cells, while 5-FU was the most cytotoxic in A549 cells. When these drugs were used in combination, the more synergistic combination in PC-3 cells was the IC₅₀ of SAQ with various concentrations of 5-FU, particularly when 5-FU was only applied 24 h later. Meanwhile for A549 the most promising combination was 5-FU with delayed SAQ, but with a weaker effect than all combinations demonstrated in PC-3 cells. These results demonstrate that SAQ could be used as a new repurposed drug for the treatment of prostate cancer and this treatment potential could be even greater if SAQ is combined with the anticancer drug 5-FU, while for lung cancer it is not as efficient and, therefore, not of as much interest.     

Molecular mechanics analysis of drug-resistant mutants of HIV protease

Drug-resistant mutants of HIV-1 protease limit the long-termeffectiveness of current anti-viral therapy. In order to studydrug resistance, the wild-type HIV-1 protease and the mutantsR8Q, V32I, M46I, V82A, V82I, V82F, I84V, V32I/I84V and M46I/I84Vwere modeled with the inhibitors saquinavir and indinavir usingthe program AMMP. A new screen term was introduced to reproducemore correctly the electron distribution of atoms. The atomicpartial charge was represented as a delocalized charge distributioninstead of a point charge. The calculated protease–saquinavirinteraction energies showed the highly significant correlationof 0.79 with free energy differences derived from the measuredinhibition constants for all 10 models. Three different protonationstates of indinavir were evaluated. The best indinavir modelincluded a sulfate and gave a correlation coefficient of 0.68between the calculated interaction energies and free energiesfrom inhibition constants for nine models. The exception wasR8Q with indinavir, probably due to differences in the solvationenergy. No significant correlation was found using the standardmolecular mechanics terms. The incorporation of the new screencorrection resulted in better prediction of the effects of inhibitorson resistant protease variants and has potential for selectingmore effective inhibitors for resistant virus.     

沙奎那韦中间体合成工艺改进

治疗艾滋病的沙奎那韦的中间体———(3S,4 aS,8 aS)-2〔-(2R,3S)-3氨-基-2羟-基-4苯-基丁基〕-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅱ)是通过(2S,3S)-4氯--3羟-基-1苯-基丁烷-2氨-基甲酸苄酯(Ⅲ)和(3S,4 aS,8 aS)-N-叔丁基-十氢异喹啉-3-羧酰胺(Ⅴ)反应得到的。该文对工艺进行了如下改进:Ⅲ的环化和与Ⅴ的反应合并为“一锅煮”工艺,去除原有文献报道的柱层析过程,只需洗去氢氧化钾的分液操作,直接加入w(Pd)=10%的Pd/C催化剂,室温反应12 h即脱去保护基。反应完毕后,以乙腈重结晶即得到目标产物Ⅱ。改进后的工艺总产率达到87%,w(Ⅱ)=98.5%。该法原则上适用于多种H IV蛋白酶抑制剂的合成。