药学学报
藥學學報
약학학보
ACTA PHARMACEUTICA SINICA
2008年
7期
707-718
,共12页
王琳%张兴权%陈鸿珊%陶佩珍%李燕%白玉%扈金萍%马涛%邢振堂%彭宗根%周春梅%高琦%刘刚
王琳%張興權%陳鴻珊%陶珮珍%李燕%白玉%扈金萍%馬濤%邢振堂%彭宗根%週春梅%高琦%劉剛
왕림%장흥권%진홍산%도패진%리연%백옥%호금평%마도%형진당%팽종근%주춘매%고기%류강
消旋去甲胡桐素A%人免疫缺陷病毒%协同作用%急性毒性
消鏇去甲鬍桐素A%人免疫缺陷病毒%協同作用%急性毒性
소선거갑호동소A%인면역결함병독%협동작용%급성독성
racemic 11-demethylcalanolide A%HIV-1%synergistic effects%acute toxicity in mice
本文发展一个实用改进方法以合成具有抗人免疫缺陷病毒(HIV-1)的天然产物的类似物11-去甲胡桐素A[(±)-1],方法改进包括以间苯三酚为起始原料与正丁酰乙酸乙酯在饱和氯化氢甲醇存在下,经过Pechmann反应生成5,7-双羟基-4-正丙基香豆素(3),再与巴豆酸用多聚磷酸作溶剂及催化剂进行酰化,同时分子内环合得到收率为70%关键中间体苯并二氢吡喃酮(4),并与缩醛1,1-二乙氧基-3-甲基-2-丁烯用微波辅助催化得到苯并吡喃(6),最后用Luche还原以CeCl3·7H2O作催化剂,在低温下经NaBH4选择性还原化合物(6)得到目标产物即消旋11-去甲胡桐素A(±)-1.上述4步反应总收率32%,比原方法提高1倍.体外研究表明(±)-1对HIV-1(野株)及耐药株均有明显抑制逆转录酶和P24抗原的活性,(±)-1在细胞培养内分别与作用机制不同的3种治疗艾滋病药物(AZT、T-20、Indinavir)都有明显的协同作用.小鼠急性毒性,(±)-1的LD50灌胃给药为735.65mg·kg-1,腹腔给药为525.10mg·kg-1.小鼠灌胃给与(±)-1血浆峰浓度(Cmax)与药时曲线面积AUC0-∞分别为0.54μg·mL-1及1.08(μg·mL-1)·h.为了初步观察(±)-1的体内药效,采用血清药理学方法,小鼠腹腔注射1次(±)-1或临床有效对照药奈韦拉平,30min和60min后血清有相似的抑制HIV-1逆转录酶活性.实验结果提示去甲11-胡桐素A值得进一步研究.
本文髮展一箇實用改進方法以閤成具有抗人免疫缺陷病毒(HIV-1)的天然產物的類似物11-去甲鬍桐素A[(±)-1],方法改進包括以間苯三酚為起始原料與正丁酰乙痠乙酯在飽和氯化氫甲醇存在下,經過Pechmann反應生成5,7-雙羥基-4-正丙基香豆素(3),再與巴豆痠用多聚燐痠作溶劑及催化劑進行酰化,同時分子內環閤得到收率為70%關鍵中間體苯併二氫吡喃酮(4),併與縮醛1,1-二乙氧基-3-甲基-2-丁烯用微波輔助催化得到苯併吡喃(6),最後用Luche還原以CeCl3·7H2O作催化劑,在低溫下經NaBH4選擇性還原化閤物(6)得到目標產物即消鏇11-去甲鬍桐素A(±)-1.上述4步反應總收率32%,比原方法提高1倍.體外研究錶明(±)-1對HIV-1(野株)及耐藥株均有明顯抑製逆轉錄酶和P24抗原的活性,(±)-1在細胞培養內分彆與作用機製不同的3種治療艾滋病藥物(AZT、T-20、Indinavir)都有明顯的協同作用.小鼠急性毒性,(±)-1的LD50灌胃給藥為735.65mg·kg-1,腹腔給藥為525.10mg·kg-1.小鼠灌胃給與(±)-1血漿峰濃度(Cmax)與藥時麯線麵積AUC0-∞分彆為0.54μg·mL-1及1.08(μg·mL-1)·h.為瞭初步觀察(±)-1的體內藥效,採用血清藥理學方法,小鼠腹腔註射1次(±)-1或臨床有效對照藥奈韋拉平,30min和60min後血清有相似的抑製HIV-1逆轉錄酶活性.實驗結果提示去甲11-鬍桐素A值得進一步研究.
본문발전일개실용개진방법이합성구유항인면역결함병독(HIV-1)적천연산물적유사물11-거갑호동소A[(±)-1],방법개진포괄이간분삼분위기시원료여정정선을산을지재포화록화경갑순존재하,경과Pechmann반응생성5,7-쌍간기-4-정병기향두소(3),재여파두산용다취린산작용제급최화제진행선화,동시분자내배합득도수솔위70%관건중간체분병이경필남동(4),병여축철1,1-이을양기-3-갑기-2-정희용미파보조최화득도분병필남(6),최후용Luche환원이CeCl3·7H2O작최화제,재저온하경NaBH4선택성환원화합물(6)득도목표산물즉소선11-거갑호동소A(±)-1.상술4보반응총수솔32%,비원방법제고1배.체외연구표명(±)-1대HIV-1(야주)급내약주균유명현억제역전록매화P24항원적활성,(±)-1재세포배양내분별여작용궤제불동적3충치료애자병약물(AZT、T-20、Indinavir)도유명현적협동작용.소서급성독성,(±)-1적LD50관위급약위735.65mg·kg-1,복강급약위525.10mg·kg-1.소서관위급여(±)-1혈장봉농도(Cmax)여약시곡선면적AUC0-∞분별위0.54μg·mL-1급1.08(μg·mL-1)·h.위료초보관찰(±)-1적체내약효,채용혈청약이학방법,소서복강주사1차(±)-1혹림상유효대조약내위랍평,30min화60min후혈청유상사적억제HIV-1역전록매활성.실험결과제시거갑11-호동소A치득진일보연구.
An improved and practical synthesis of racemic 11-demethylcalanolide A [(±)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5, 7,-dihydroxy-4-n-propylcoumarin(3). Poly phosphoric acid (PPA) catalyzed acylation of compound(3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone(4). A microwave assisted synthetic method preparing chromene(6) using chromenynation of chromanone(4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene(6) using NaBH<,4> with CeCl3·7H2O preferably gave (±)-1. The overall yield of this four step synthesis of (±)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (±)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65mg·kg-1 and 525.10mg·kg-1, respectively. The C<,max> and AUC<,0-∞> were 0.54μg·mL-1 and 1.08(μg·mL-1)·h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100mg·kg-1 (±)-1 once intraperitoneally were similar to that of 5mg·kg-1 of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (±)-1 was warranted.
