TW201514183A - 喜樹鹼的新穎２０（ｓ）－磺基脒衍生物及其抗腫瘤劑的用途 - Google Patents
喜樹鹼的新穎２０（ｓ）－磺基脒衍生物及其抗腫瘤劑的用途 Download PDFInfo
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- TW201514183A TW201514183A TW103132504A TW103132504A TW201514183A TW 201514183 A TW201514183 A TW 201514183A TW 103132504 A TW103132504 A TW 103132504A TW 103132504 A TW103132504 A TW 103132504A TW 201514183 A TW201514183 A TW 201514183A
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本發明係關於一種喜樹鹼(1)的新穎20-磺基脒衍生物、其合成方法、及其作為抗腫瘤劑，例如用以治療鼻咽、肺、乳房或前列腺癌的抗腫瘤劑之用途。
Description
本發明係關於一種喜樹鹼的新穎20-磺基脒衍生物(1)、其合成方法及其作為抗腫瘤劑的用途。
喜樹鹼(CPT，1，圖1)係一種具有值得注意的抗腫瘤效應之天然產生的生物鹼1-3。其抗腫瘤活性已經歸因於其藉由穩定化不可逆的藥物-酵素-DNA三元複體及防止由Topo I所引發的單股DNA斷裂之再連接來干擾DNA拓撲異構酶I(Topo I)之催化性循環的能力4,5。在過去數十年間，密集的藥物合成化學研究已導致有效力的1-衍生物，包括現在臨床使用來治療卵巢、小細胞肺及結腸癌的托僕泰肯(topotecan)(2)及依立泰肯(irinotecan)(3)。同樣地，數種衍生物諸如吉麻泰肯(gimatecan)(4)、CDK-602(5)及BNP-1350(6)已在多種臨床前或臨床發展階段6-8。雖然臨床使用的1-衍生物仍然係有前景的抗腫瘤劑種類，但其治療用途已經由於毒性爭議、及由於差的水溶解度之傳遞問題、和由於該開環的
羧酸鹽對血清白蛋白的優先結合之活性內酯形式不穩定性而受到嚴苛地阻礙9,10。
已經探索出數種方法來改良1-家族的抗腫瘤效率，包括發展出前藥體(軛合物及鍵結聚合物的喜樹鹼類)、新型調配物(脂粒或微粒載劑)及合成親油性喜樹鹼類11-13。這些策略大部分旨在維持於血漿(plasma compartment)中的活性封閉式內酯形式。自由態20-羥基由於會形成分子內氫鍵而偏愛內酯開環14，同時此基團之醯化應該會穩定化該封閉式內酯部分15。再者，在所引進的酯部分中之立體位阻效應(steric bulk)可係想要的，其將阻礙該酯鍵由多種酵素包括羧基酯酶類水解，因此減低毒性。更確切來說，我們自己的結果16,17、和其它具有20(S)-O-醯基酯類18,19、20(S)-O-碳酸酯連結的三胜肽軛合物20、及20(S)-O-連結的醣共軛分子21之結果已支持該酯化的1-衍生物對有效力的活性之重要性。與未修改的1比較，20-羥基的酯化亦提高血漿穩定性及增進活體內抗腫瘤活性。
脒類已熟知為重要的藥效團22-25及已廣泛使用在生物活性化學物質及藥物分子設計中。同樣地，將磺基引進生物活性官能基片段中會在化合物的生物活性上產生明顯改變26,27；因此，磺基脒類對最佳化生物活性分子來說可係有用的結構模體(structure motifs)。因為此基團亦相當龐大，其可立體位阻地防止大酵素容易地水解1的20(S)-O-醯基酯，此亦應該減低毒性。比較上，從3之水解所形成的化合物SN-38相當毒28。考慮到這些考量，我們假定在1的20-位置
處引進磺基脒基團可導致改良效力及減低毒性，和最佳化新型的1-相關之抗癌候選藥物的物理化學性質。因此，在本研究中，我們經由Cu催化式一鍋反應將磺基脒官能基片段併入1的C-20位置處29及合成一新穎系列的1之衍生物作為有潛力的抗腫瘤劑。
本發明係關於一種喜樹鹼(1)的新穎20-磺基脒衍生物、其合成方法、及其作為抗腫瘤劑的用途。
在本發明中所提供的化合物具有下列結構：
其中R1係H、C1-C6烷基、或苯基C1-C3烷基；R2係羥基C1-C6烷基、(CH3)kH3-kSi、苯基、C1-C3烷基苯基、C1-C3烷氧基苯基、氟苯基、氯苯基、溴苯基、(CH2)j-O-(CH2)i-R11，其中k係0、1、2或3；j係1-5；i係
0-5；及R11係或，其中R8、R10、R12及
R13各自獨立地係H或C1-C6烷基；
R3係H、NO2、或
，其中R8及R10係如上述所定義；
R4係H或NO2；
R5係H、C1-C6烷基、或
R6係H、OH或
R7係H、C1-C6烷基或C1-C6烷氧基；及R9係H、C1-C6烷基、苯基、C1-C3烷基苯基、C1-C3烷氧基苯基、氟苯基、氯苯基、溴苯基、吡啶基、萘基、呋喃基、
噻吩基、吡咯基、或，其中R8
及R10各自獨立地係H或C1-C6烷基；n係0-3；m係1-5；X係O或S；Y係O；Z係O；及W係O。
較佳的是，R3、R4、R5、R6及R7全部係H；n係0；m係1；及X係O。更佳的是，R9係C1-C6烷基、C1-C3
烷基苯基、C1-C3烷氧基苯基、氟苯基、氯苯基或
最佳的是，R2係羥基C1-C6烷基、苯基、C1-C3烷氧基苯基或(CH2)j-O-(CH2)i-R11，其中j係1；i係0或1；及R11係
或，其中R8、R10、R12及R13全部係甲基。
再者，R1較佳為H、C1-C6烷基或苯基甲基。更佳的是，R2係對-甲氧基苯基。再者，R2係(CH2)j-O-(CH2)i-R11，其中j
係1；i係0或1；及R11係或，其中R8、
R10、R12及R13全部係甲基。
較佳的是，R2係對-甲氧基苯基或對-氟苯基、R1及R4二者係H、R9係對-甲基苯基、n係0、m係1及X係O。
更佳的是，R5係CH3CH2、R6係H或OH、R7係H、R2係對-甲氧基苯基、及R3係H。再者，R5係CH3CH2、R6係H、R7
係H、R2係對-甲氧基苯基、及R3係
當R2係對-甲氧基苯基或對-氟苯基、R1及R4二者係H、R9係對-甲基苯基、n係0、m係1及X係O時，較佳的是，i)R5及R7二者係H、R6係OH、R2係對-甲氧基苯基、
及R3係，其中R8係甲基；ii)R3、R5及R6全部係H、
R7係甲基、R2係對-甲氧基苯基；或iii)R3、R5、R6及R7全部係H、R2係對-氟苯基。
本發明亦提供一種本發明之前述化合物的用途，其係使用來製造用以治療癌的藥劑。
較佳的是，該癌係結腸癌、鼻咽癌、肺癌、乳房癌、前列腺癌或卵巢癌。
本發明進一步提供一種用以治療癌的方法，其包括將一有效量之本發明的前述化合物給藥至需要其之對象。
圖1顯示出喜樹鹼(1)、托僕泰肯(2)及依立泰肯(3)、吉麻泰肯(4)、CDK-602(5)及BNP-1350(6)的結構。
圖2顯示出化合物9a在人類結腸直腸HCT116癌異種
移植模型中的抗癌活性，其中該化合物9a係一種在本發明的較佳具體實例之一中所合成的新穎化合物。
圖3顯示出9a不明顯影響動物體重。
我們於此揭示出經由Cu催化式一鍋反應將磺基脒基團引進1的20-位置處以產生9a-9l作為有潛力的抗腫瘤劑。
十二種喜樹鹼(1)的新穎20-磺基脒衍生物(9a-9l)係經由Cu催化三組分反應合成。與依立泰肯(3)比較，其對A-549、DU-145、KB及抗多種藥物性(MDR)KBvin腫瘤細胞株顯示出類似或優異的細胞毒性。與1及3比較，化合物9a闡明對MDR細胞有較好的細胞毒性。機制上，9a藉由選擇性抑制拓撲異構酶(TOPO)I及啟動ATM/Chk相關的DNA損傷反應途徑引發明顯的DNA損傷。在異種移植模型中，9a在5及10毫克/公斤處闡明明顯活性而沒有明顯的副作用，此可與3在100毫克/公斤處比較。與1(LD50 56.2毫克/公斤，腹腔)及3(LD50 177.5毫克/公斤，腹腔)比較，9a在300毫克/公斤(腹腔)下顯著地顯示出無明顯毒性。完整的9a在無細胞檢定中類似於1般抑制TOPO I活性，此證實9a係一種新種類的TOPO I抑制劑。20-磺基脒1-衍生物9a值得發展作為抗癌臨床檢定候選物。
化學。如在流程1中所顯示，1的20-羥基係藉由簡單地修改該碳二醯亞胺方法，使用N,N’-二異丙基碳二醯亞胺(DIPC)與4-二甲基胺基吡啶(DMAP)之組合來酯化，以合適的產率提供N-Boc-胺基酸衍生物(7)。以在CH2Cl2中的三氟醋酸(TFA)(1：1)移除7的N-Boc基團，形成關鍵性中間物TFA鹽8。隨後，我們施加高效率的Cu催化三組分耦合反應29，其中8係與對-甲苯磺基疊氮及廣泛範圍的炔類反應，以產率35-58%獲得想要的化合物9a-9l。標的分子的結構係以1H-NMR、13C-NMR、IR及HR-MS資料標出特徵。
新型化合物的抗增生活性及結構-活性關係。使用硫羅丹明(sulforhodamine)B比色分析，以一式三份實驗試管內評估12種新穎的1-衍生物9a-l對四種人類腫瘤細胞株
KB(鼻咽)、A-549(肺)、DU-145(前列腺)及KBvin(MDR KB亞株)之抗增生活性30。使用化合物1及3作為對照。篩選結果係顯示在表1中。
全部12種新型化合物(9a-9l)對四種測試的腫瘤細胞株具有明顯的試管內細胞毒素活性，其IC50值範圍係0.026至11μM，此指示出在20-磺基脒側鏈中的R1及R2基團二者可影響該新型1-衍生物的細胞毒素活性。該等新型化合物9a-9l(除了9a對KBvin外)的效力比1小；但是，與3比較，全部的新型衍生物顯示出相等或優異的細胞毒素活性。在新近合成的衍生物當中，9a對四種測試的腫瘤細胞株係最有效力的化合物。有趣的是，與1及3比較(其IC50各別為0.12及>20μM)，9a亦顯示出對KBvin有較大的細胞毒素活性(IC50係0.026μM)。結果亦顯露出A-549細胞株比其它三種細胞株對這些化合物更敏感，此與其它1-衍生物的臨床行為一致19。
亦對1的這些新型20-磺基脒衍生物鑑別結構-活性關係(SAR)相關聯性。當R2基團係固定為苯基及改變在該磺基脒中的R1基團時，與9f(異丙基)、9h(異丁基)及9j(二級丁基)的較大烷基比較，氫(9b)及甲基(9d)提供最好的結果。在承載對-甲氧基苯基之R2基團的相應衍生物中看見類似的結果。例如，對抗A-549細胞株，其細胞毒素效力的等級次序為9a(H)>9c(甲基)>9g(異丁基)>9e(異丙基)>9i(二級丁基)。因此，對較大的細胞毒素效力來說，小的脂肪族鏈似乎係最好的R1取代基。當R1基團係保持固定及R2基團從苯基改變成對-甲氧基苯基時，該細胞毒素活性經常改良(例如，比較9b對9a，9f對9e，9h對9g，或9j對9i，對抗KBvin)。此外，與具有對-甲氧基苯基之R2基團的9k比較，承載羥甲
基R2基團的化合物9l顯示出可比較(DU-145、KB)或較大(A-549、KBvin)的細胞毒素活性。同樣地，具有苄基之R1基團的化合物9k通常具有介於具有較小(9a，9c)與較大(9e，9g，9i)的烷基R1基團之化合物間的中間效力。這些研究結果指示出該1-衍生物的細胞毒素曲線係對在C-20處之取代基的尺寸及電子密度敏感。以這些試管內結果為基準，選擇化合物9a用於活體內評估。
9a的作用機制研究。
9a在無細胞系統中之TOPO I活性抑制。具有經酯化的20-羥基之1-衍生物預計係藉由羧基酯酶類消化而啟動。為了測定完整的9a是否抑制TOPO I，使用無細胞TOPO I活性檢定，使用經純化的重組人類TOPO I。在此檢定中，超螺旋質體DNA係藉由重組的TOPO I鬆解及鏈裂。因此，使用媒劑對照或在TOPO I活性上不具有抑制效應的測試化合物可發現經鬆解及鏈裂的DNA。已知係1的前藥體之化合物3顯示出相同結果，因為其在此無細胞系統中無法啟動，因為其係藉由在細胞中的羧基酯酶類啟動。比較上，3的生物活性代謝物SN-38抑制TOPO I活性。我們顯著地發現完整的9a在此無細胞檢定中類似於1抑制TOPO I活性。我們鑑定出9a對抗TOPO I的抑制效應係呈劑量相依方式。因此，我們證實9a係新型的TOPO I抑制劑種類。
由9a誘導人類腫瘤細胞凋亡。因為A-549人類肺腺癌上皮細胞在初測細胞毒性曲線中對9a顯示出比其它經測試的癌細胞株具有較高的靈敏度，在我們的機制研究中使
用A-549細胞。最初，我們調查細胞的形態學變化。在曝露至9a後，A-549細胞顯示出細胞凋亡形態外觀，包括細胞萎縮及膜起泡(membrane blebbing)。細胞凋亡誘導係藉由以FITC-膜聯蛋白(annexin)V及碘化丙啶(propidium iodide)雙重染色進一步證實，此顯示出9a治療增加凋亡細胞的百分比(膜聯蛋白V陽性細胞群：媒劑對9a，24小時，1.1%對3.7%，P<0.01；48小時，2.0%對34.1%，P<0.001)。西方墨點(Western blot)分析顯示出經切割的凋亡蛋白酶(caspases)，該細胞凋亡的執行者(executors)，係因應9a形成，包括凋亡蛋白酶-8、-9及-3。細胞凋亡的標誌特徵PARP亦由9a啟動。這些資料闡明9a透過細胞凋亡誘導來抑制A-549細胞生長。
藉由9a啟動DNA損傷反應途徑。1的主要效應為結合至該共價的TOPO I-DNA複體及穩定化其，因此，誘導細胞週期在S期時延遲，防止DNA連接及最終導致細胞凋亡31。檢驗9a是否如1在A-549細胞中般啟動相同途徑以闡明該作用機制。首先，我們使用流式細胞測量術分析來測定9a在細胞週期分佈上的效應。如我們所預計，以9a治療24小時造成細胞總數在S及次-G1期增加。進行TOPO I媒介的DNA切割檢定以檢驗9a在細胞中是否於TOPO I活性上具有抑制效應。結果顯示出9a抑制超螺旋DNA鬆解，其係類似於1的效應。但是，9a及1二者未能解除動基體DNA(kDNA)連接，然而已知的TOPO II抑制劑鬼臼乙叉有效地阻斷kDNA之解除連接。因為已經顯示出1-TOPO I-DNA共價複體提高TOPO I經由26S蛋白酶體(proteasome)途徑之轉錄相依性降
解32，研究9a在TOPO I及TOPO II的表現性位準上之效應。西方墨點分析顯示出在8小時治療後9a明顯抑制TOPO I之蛋白質位準，及在24小時治療後稍微影響TOPO II及TOPO II的位準。這些結果明確地闡明9a抑制TOPO I而沒有干擾TOPO II活性。化合物9a直接作用在TOPO I上及造成共價的TOPO I-DNA複體累積，接著蛋白酶體的TOPO I降解，其係與1相同的效應及促成9a的細胞毒性。
化合物1可引發DNA損傷及啟動ATM-Chk2 DNA損傷反應途徑而在癌細胞中觸發細胞凋亡途徑33。我們發現在以9a治療0.5小時後，ATM在Ser1981殘基處進行磷酸化。ATM激酶之活化係藉由偵測下游受動器，Chk1、Chk2及組織蛋白H2AX的磷酸化證實。H2AX在Ser139殘基(γH2AX)處的磷酸化指示出9a造成DNA雙股斷裂。p53在DNA損傷功能上發揮關鍵角色，包括細胞週期調控及細胞凋亡觸發34。p53的調升及磷酸化由9a大大地提高。p53下游細胞凋亡蛋白質諸如PUMA及BAX亦由9a顯著地增加。再者，9a調升FADD，一種死亡受體媒介的外因性細胞凋亡組分；及藉由防止粒腺體損傷成分漏出而調降該促存活蛋白質Bcl-xL及Bcl-2。
合起來說，化合物9a(YQL-9a)直接抑制TOPO I活性及削弱TOPO I表現性，此引發細胞週期在S期延遲和啟動DNA損傷反應途徑，及隨後啟動細胞凋亡途徑。我們的資料支持9a的優異性超過母化合物1，此建議9a係一種優良有潛力的抗癌候選藥物。因此，我們進一步研究9a的抗腫瘤活
性及毒物學之活體內評估。
9a的活體內抗腫瘤活性。根據在表2中的方案，使用人類結腸直腸腺癌細胞株HCT116進行異種移植模型抗腫瘤檢定。該31天的研究係使用四組承載所建立的HCT116異種移植物之老鼠(n=8)，其中該移植物在第1天時具有平均體積大約200立方毫米。對每個治療群組測量腫瘤生長及動物體重變化，每星期三次(圖2及3)。化合物9a係以5及10毫克/公斤每天一次(QD)靜脈內(i.v.)給藥7天，然後腹膜內(i.p.)至結束。八隻的二隻及八隻老鼠的三隻各別在5毫克/公斤及10毫克/公斤劑量組中顯示出完全消退。體重在任一劑量下都沒有明顯變化。使用3的實驗對照在每星期一次(QWK)100毫克/公斤的劑量下亦具有抗腫瘤活性(P<0.001)，及三隻老鼠顯示出完全消退，此支持我們的活體內評估之準確性。以Student-t檢定評估為基準，9a在5毫克/公斤(P<0.01)及10毫克/公斤(P<0.001)下具有明顯的活體內抗腫瘤活性，沒有明顯的症狀及急性過敏反應跡象。
9a在老鼠中的毒物學評估。病理學評估9a在老鼠中的急毒性。將六十隻8週大的公BALB/c老鼠隨機分成六組(n=10)，在第零天時腹膜內接收0(僅有媒劑)、30、100、200或300毫克/公斤的9a。一組保持沒有治療作為正常對照。全部經治療的動物皆顯示出無急性過敏反應、過敏反應或明顯的體重減低，及其係與正常對照動物一樣健康，此指示出明顯減低毒性，與1(LD50=56.2毫克/公斤，腹腔)及3(LD50=177.5毫克/公斤，腹腔)比較35。在實驗時期結束時，全部動物皆安樂死及根據由Shackelford等人所描述的指導方針對來自肝、肺、腎及脾的組織進行組織病理學評估36，和對症狀的病灶分級。該組織病理學評估包括：1)在肝中，肝醣沈著、炎症細胞浸潤及局限性壞死；2)在腎中，腎小管之恢復、炎症細胞浸潤及慢性進行性腎病；及3)在肺中，炎症細胞浸潤及腺瘤。雖然在來自經9a治療及未治療的老鼠二者組織中皆觀察到少數微觀病灶，全部病灶皆視為自發性病灶及與9a給藥不相關。因此，根據肝、脾、腎及肺參數，經9a治療的動物顯示出無副作用。因此，該等動物明顯對以300毫克/公斤的9a治療具耐受性，此預告一可接受的安全曲線。
我們假定對正常組織的毒物學改良可與在1的20-位置處引進磺基脒側鏈相關。驚人的是，此修改不會破壞對TOPO I的抑制效應及亦可防止內酯開環而造成封閉式內酯部分之穩定化及促成1之較好的生物活性。包括代謝及藥物動力學評估和在1的C-7位置處引進磺基脒側鏈之進一步研
究現在正在進行中，以解決此假定。
總而言之，新穎的20(S)-磺基脒1-衍生物系列係經設計及以Cu催化式一鍋反應之關鍵步驟合成。與3比較，全部12種衍生物皆顯示出可比較或優異的細胞毒素活性。顯著的是，化合物9a對抗多種藥物性KBvin細胞係與1一樣有效力及比3極度更有效力。該新型衍生物的IC50值範圍係0.026至11μM，此指示出在20-磺基脒側鏈中的R1及R2基團可大大地影響該新型1-衍生物的細胞毒素活性，此導致重要的SAR訊息。同樣地，5毫克/公斤及10毫克/公斤的9a闡明在承載所建立的人類HCT116結腸直腸腺癌之老鼠中有明顯的抗腫瘤活性，且在全部所測試的劑量下於體重上無明顯變化。此外，八隻的二隻及八隻老鼠的三隻各別在5毫克/公斤及10毫克/公斤劑量組中顯示出完全消退。對老鼠的肝、脾、肺及腎之組織病理學的急毒性評估顯示出以300毫克/公斤的9a治療無副作用。以這些正面結果為基準，確切地保證9a相關的化合物進一步發展作為有潛力的抗癌臨床試驗候選物。
一般化學訊息。N-Boc-胺基酸及TFA係從GL Biochem(上海)Company購買。DIPC及DMAP係從Sigma Chemical Company(中國)購買。其它試劑及溶劑係從商業來源購買及如所接收時般使用。開始的1係從中國藥用植物喜樹(C.acuminata)中分離出，及在使用前進行純化(純度>98%)。以矽凝膠板，使用矽凝膠60 GF254(Qingdao Haiyang
Chemical Co.,Ltd.)進行分析級薄層層析法(TLC)及製備級薄層層析法(PTLC)。在Kofler熔點裝置上取得熔點及未經校正。IR光譜係在NIC-5DX分光光度計上獲得。在ZAB-HS及Bruker Daltonics APEXII49e儀器上進行MS分析。在Bruker AM-400光譜儀上，以400MHz記錄NMR光譜，使用TMS作為參考(Bruker Company，美國)。全部的測試化合物之純度係藉由配備有C-18結合相管柱(Eclipse Plus C18，5μM顆粒尺寸，4.6毫米×250毫米)的HPLC(Agilent Technologies 1100系列)測定。以MeOH及水作為動相進行梯度沖提及在254奈米下監視。全部的測試化合物之純度係>95%。
關鍵中間物7及8之合成。在室溫下，將適當的N-BoC-胺基酸(3.13毫莫耳)溶解在200毫升無水CH2Cl2中。在0℃下，將DIPC(0.5毫升，3.13毫莫耳)、DMAP(3.13毫莫耳)及1(3.13毫莫耳)加入至此溶液16。允許該反應混合物加熱至室溫及遺留16小時。然後，以0.1N HCl清洗該溶液，乾燥，及在減壓下蒸發以產生白色固體，從MeOH再結晶其以提供N-BoC-胺基酸1酯衍生物(7)，產率56-87%。隨後，將此中間物(7，1毫莫耳)溶解在CH2Cl2(10毫升)與TFA(10毫升)之混合物中及在室溫下攪拌1小時。移除溶劑及剩餘固體係從CH2Cl2及二乙基醚再結晶以提供相應的TFA鹽(8)，產率57-82%。
化合物9a-9l的一般合成程序。將三乙基胺(1.2毫莫耳)慢慢加入至TFA鹽8(0.5毫莫耳)在CH2Cl2(35毫升)中的懸浮液，及攪拌此混合物10分鐘直到獲得一透明溶液。
在N2環境下加入炔(0.5毫莫耳)、對-甲苯磺基疊氮(0.6毫莫耳)及CuI(0.05毫莫耳)。在室溫下攪拌該反應混合物2-6小時。在反應完成後，如藉由TLC監視，藉由加入CH2Cl2(4毫升)及NH4Cl水溶液(6毫升)稀釋該反應混合物。攪拌該混合物額外30分鐘及分離成二層。該水層係以CH2Cl2(3毫升×3)萃取。在MgSO4上乾燥該結合的有機層，過濾及在真空中濃縮。粗產物殘餘物係藉由快速管柱層析法，在Si凝膠上，使用CHCl3-MeOH(10：1~20：1)作為沖提液純化，以提供9a-9l。
化合物9a. 產率52%；m.p.129-131℃；tR-HPLC,3.59min(95.4%)；IR(KBr)ν cm-1：3376,3285,2932,1753,1663,1612,1510,1455,1401,1277,1249,1144,1089,1053,892,789,688,553；1H NMR(CDCl3,400MHz)δ：8.39(s,1H,C7-H),8.24(d,1H,J=8.8Hz,C9-H),7.94(d,1H,J=8.0Hz,C12-H),7.85(t,1H,J=7.6Hz,C11-H),7.82(d,2H,J=8.0Hz,Ts-H),7.68(t,1H,C10-H),7.32(s,1H,C14-H),7.24(d,2H,J=8.0Hz,Ts-H),7.04(d,2H,J=8.4Hz,-PhOCH3),6.83(d,2H,J=8.8Hz,-PhOCH3),5.52(ABq,2H,J=17.2,C17-H),5.26(s,2H,C5-H),4.17-4.31(m,4H,C23,30-H),3.73(s,3H,-PhOCH 3),2.39(s,3H,Ts-CH 3),2.11-2.21(m,2H,C18-H),0.91(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ：167.6,167.1,166.8,159.4,157.1,152.2,148.9,146.7,144.8,131.3,131.2,130.8,129.7,129.2,128,4,128.2,126.5,142.4,140.2,120.1,114.9,95.6,76.7,67.2,55.2,50.0,43.3,38.5,31.8,21.5,7.5；C38H34N4O8依HRMS的計算值：729.1990[M+Na]+，實驗
值：729.2002[M+Na]+.
化合物9b. 產率54%；m.p.132-134℃；tR-HPLC,3.33min(100%)；IR(KBr)ν cm-1：3394,3339,3061,2973,2926,1753,1663,1614,1557,1498,1453,1401,1278,1232,1145,1089,1054,985,813；1H NMR(CDCl3,400MHz)δ：8.39(s,1H,C7-H),8.24(d,1H,J=8.8Hz,C9-H),7.94(d,1H,J=8.0Hz,C12-H),7.82-7.86(m,3H,C11-H,Ts-H),7.68(t,1H,C10-H),7.33(s,1H,C14-H),7.28-7.32(m,3H,Ph-H),7.23(d,2H,J=8.0Hz,Ts-H),7.18(d,2H,J=8.0Hz,Ph-H),5.51(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.20-4.31(m,4H,C23,30-H),2.39(s,3H,Ts-CH 3),2.11-2.22(m,2H,C18-H),0.91(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ 167.6,166.8,166.5,157.2,152.2,148.9,146.4,144.8,132.3,131.2,130.8,130.1,129.7,129,5,128.3,126.5,142.4,140.2,120.2,95.6,76.2,67.2,50.0,43.3,39.3,31.7,21.5,7.5；C37H32N4O7S依HRMS的計算值：677.2064[M+Na]+，實驗值：677.2051[M+Na]+.
化合物9c. 產率55%；m.p.112-114℃；tR-HPLC,2.92min(96.9%)；IR(KBr)ν cm-1：3371,3261,2931,1751,1662,1611,1548,1402,1277,1249,1144,1085,814,759,689；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),8.26(d,1H,J=8.8Hz,C9-H),7.93(d,1H,J=8.0Hz,C12-H),7.80-7.83(m,3H,C11-H,Ts-H),7.67(t,1H,C10-H),7.36(s,1H,C14-H),7.22(d,2H,J=8.0Hz,Ts-H),7.02(d,J=8.8Hz,-PhOCH3),
6.81(d,2H,J=8.8Hz,-PhOCH3),5.50(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.86(m,1H,C23-H),4.23(s,2H,C30-H),3.74(s,3H,-PhOCH 3),2.39(s,3H,Ts-CH3),2.11-2.21(m,2H,C18-H),1.47(m,3H,L-alanine-CH 3 ),0.91(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ 170.8,166.8,166.3,159.4,157.2,152.1,148.9,146.6,144.7,131.4,131.1,130.7,130.5,129.8,129.5,129.1,128.4,128.2,128.0,126.4,124.3,142.2,140.3,120.8,114.8,95.5,67.2,55.2,50.0,49.7,38.6,31.7,21.5,17.4,7.5；C39H36N4O8S依HRMS的計算值：743.2146[M+Na]+，實驗值743.2157[M+Na]+.
化合物9d. 產率57%,108-110℃；tR-HPLC,3.55min(100%)；IR(KBr)ν cm-1：3395,3311,2979,1755,1667,1619,1541,1402,1277,1231,1143,1085,1058,813,755,702；1H NMR(CDCl3,400MHz)δ 8.39(s,1H,C7-H),8.22(d,1H,J=8.4Hz,C9-H),7.94(d,1H,J=8.0Hz,C12-H),7.80-7.89(m,3H,C11-H,Ts-H),7.69(t,1H,C10-H),7.38-7.41(m,2H,Ph-H),7.36(s,1H,C14-H),7.30-7.33(m,3H,Ph-H),7.25(d,2H,J=8.0Hz,Ts-H),5.51(ABq,2H,J=17.2Hz,C17-H),5.25(s,2H,C5-H),4.82(m,1H,C-23H),4.33(s,2H,C30-H),2.40(s,3H,Ts-CH 3),2.11-2.21(m,2H,C18-H),1.44(d,3H,L-alanine-CH 3),0.89(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ 170.0,166.7,165.7,157.2,152.2,148.9,146.7,144.6,132.6,131.1,130.7,130.2,129.8,129.5,129.4,129.2,128.4,128.2,128.1,126.4,142.2,140.2,120.2,95.3,67.2,50.0,49.9,
39.5,31.7,21.5,17.3,7.5；C38H34N4O7S依HRMS的計算值：691.2221[M+H]+，實驗值：691.2206[M+H]+.
化合物9e. 產率55%；m.p.118-120℃；tR-HPLC,4.40min(95.2%)；IR(KBr)ν cm-1：3392,3259,2931,1749,1665,1615,1541,1511,1401,1277,1249,1142,1086,812,689,553；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),8.20(d,1H,J=8.8Hz,C9-H),7.94(d,1H,J=8.0Hz,C12-H),7.82(t,1H,C11-H),7.72(d,2H,J=8.4Hz,Ts-H),7.66(t,1H,C10-H),7.42(d,2H,J=8.4Hz,-PhOCH3),7.36(s,1H,C14-H),7.17(d,2H,J=8.0Hz,Ts-H),7.04(d,2H,J=8.8Hz,-PhOCH3),5.51(ABq,2H,J=17.6Hz,C17-H),5.26(s,2H,C5-H),4.61(m,1H,C23-H),4.33(s,2H,C30-H),3.80(s,3H,-PhOCH 3),2.36(s,3H,Ts-CH 3),2.18-2.20(m,3H,C18-H,L-valine-CH(CH3)2),0.91(m,3H,C19-H),0.74-0.89(m,6H,L-valine-CH(CH 3)2)；13C NMR(100MHz,CDCl3)δ 168.4,166.9,166.6,159.6,157.2,152.2,148.9,146.7,144.1,131.7,131.0,130.6,129.8,129.0,128.4,128.3,128.1,128.0,126.2,142.2,140.2,120.8,115.1,95.5,76.3,67.4,59.2,55.3,50.1,38.8,31.7,31.0,21.4,17.7,7.5；C41H40N4O8S依HRMS的計算值：749.2640[M+H]+，實驗值：749.2648[M+H]+.
化合物9f. 產率53%；m.p.112-114℃；tR-HPLC,4.53min(95.1%)；IR(KBr)ν cm-1：3399,3263,2964,1752,1666,1620,1561,1534,1455,14399,1277,1256,1141,1085,992,806；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),8.20
(d,1H,J=8.8Hz,C9-H),7.93(d,1H,J=8.0Hz,C12-H),7.80(t,1H,C11-H),7.73(d,2H,Ts-H),7.66(t,1H,C10-H),7.48-7.53(m,5H,Ph-H),7.36(s,1H,C14-H),7.16(d,2H,J=8.0Hz,Ts-H),5.51(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.60(m,1H,C23-H),4.23(s,2H,C30-H),2.35(s,3H,Ts-CH 3),2.18-2.20(m,3H,C18-H,L-valine-CH(CH3)2),0.91(m,3H,C19-H),0.74-0.89(m,6H,L-valine-CH(CH 3)2)；13C NMR(100MHz,CDCl3)δ 168.4,166.6,166.3,157.2,152.1,148.9,146.6,144.1,133.0,131.0,130.6,130.4,129.8,129.3,129.0,128.4,128.3,128.0,126.4,140.3,120.8,95.5,67.3,59.1,50.0,39.6,31.7,31.0,21.4,17.5,7.4；C40H38N4O7S依HRMS的計算值：719.2534[M+H]+，實驗值：719.2517[M+H]+.
化合物9g. 產率54%；m.p.130-132℃；tR-HPLC,3.78min(96.2%)；IR(KBr)ν cm-1：3343,3262,2966,2930,1750,1660,1615,1558,1459,1278,1248,1148,1088,814,687；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),8.22(d,1H,J=8.4Hz,C12-H),7.92(d,1H,J=8.0Hz,C9-H),7.82(t,1H,C11-H),7.75(d,1H,J=8.0Hz,C11-H),7.65(t,1H,C10-H),7.30(d,2H,J=8.0Hz,Ts-H),7.25(s,1H,C14-H),7.02(d,2H,J=8.8Hz,-PhOCH3),6.77(d,2H,J=8.8Hz,-PhOCH3),5.32(Abq,2H,J=17.6Hz,C17-H),5.22(s,2H,C5-H),4.24-4.29(m,3H,C23,C30-H),3.74(s,3H,-PhOCH 3),2.42(s,3H,Ts-CH 3),2.33(m,3H,C18-H,
L-leucine-CH 2CH(CH3)2),1.20(m,1H,
L-leucine-CH2 CH(CH3)2),0.92(t,3H,C19-H),0.85(m,6H,L-leucine-CH(CH 3)2)；13C NMR(100MHz,CDCl3)δ：170.6,167.0,159.3,157.0,152.1,148.8,146.6,145.1,143.3,131.1,131.0,129.8,129.6,129.0,128.3,128.1,128.0,126.4,126.3,123.9,142.1,140.2,119.9,114.8,96.2,67.1,55.2,50.0,42.1,40.8,38.6,31.7,24.8,22.6,21.5,7.5；C42H42N4O8S依HRMS的計算值：763.2796[M+H]+，實驗值：763.2776[M+H]+.
化合物9h. 產率48%；m.p.125-127℃；tR-HPLC,3.82min(97.0%)；IR(KBr)ν cm-1：3391,3238,2955,1754,1664,1603,1542,1498,1402,1279,1235,1143,1086,1040,810,693；1H NMR(CDCl3,400MHz)δ 8.39(s,1H,C7-H),8.29(d,1H,J=8.4Hz,C9-H),7.93(d,1H,J=8.0Hz,C12-H),7.83(t,1H,C11-H),7.76(d,2H,J=8.4Hz,Ts-H),7.66(t,1H,C10-H),7.36(s,1H,C14-H),7.25-7.20(m,3H,Ts-H,Ph-H),7.14-7.12(m,4H,Ph-H),5.48(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.88(m,1H,C23-H),4.03-4.36(m,2H,C30-H),2.34(s,3H,Ts-CH 3),2.11-2.21(m,2H,C18-H),1.56-1.79(m,2H,L-leucine-CH 2CH(CH3)2),1.48(m,1H,L-leucine-CH(CH3)2),0.93(m,3H,C19-H),0.83-0.93(m,6H,L-leucine-CH(CH 3)2)；13C NMR(100MHz,CDCl3)δ：170.6,166.9,166.3,157.3,152.1,148.8,146.6,145.1,132.5,131.0,130.0,129.8,129.6,129.4,129.0,128.3,128.1,128.0,126.4,140.3,120.1,96.1,67.2,52.3,50.0,42.1,40.8,39.5,31.7,24.8,22.8,21.5,7.5；C41H40N4O7S依HRMS的計算值：733.2690
[M+H]+，實驗值：733.2670[M+H]+.
化合物9i. 產率58%；m.p.127-129℃；tR-HPLC,4.95min(95.2%)；IR(KBr)ν cm-1：3339,3259,2932,1752,1666,1617,1514,1459,1402,1279,1250,1140,1085,1038,896,753,677,553；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),8.19(d,1H,J=8.4Hz,C9-H),7.94(d,1H,J=8.4Hz,C12-H),7.81(t,1H,C11-H),7.74(d,2H,J=8.0Hz,Ts-H),7.68(t,1H,J=8.0Hz,C10-H),7.40(d,2H,J=8.4Hz,-PhOCH3),7.36(s,1H,C14-H),7.17(d,2H,J=8.0Hz,Ts-H),7.03(d,2H,J=8.8Hz,-PhOCH3),5.50(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.66(m,1H,C23-H),4.33(s,2H,C30-H),3.73(s,3H,-PhOCH 3),2.39(s,3H,Ts-CH 3),2.11-2.21(m,2H,C18-H),1.92-1.98(m,1H,L-isoleucine-CH(CH3)CH2CH3),0.78-1.26(m,11H,C19-H,L-isoleucine-H)；13C NMR(100MHz,CDCl3)δ 168.2,166.6,166.4,159.6,157.2,152.1,148.9,146.7,144.8,131.7,131.0,129.7,129.6,129.0,128.3,128.2,128.0,126.4,124.6,142.4,140.2,120.8,115.1,95.5,67.5,58.3,55.3,50.1,42.1,38.9,37.9,31.8,24.9,21.5,15.0,11.3,7.4；C42H42N4O8S依HRMS的計算值：763.2796[M+H]+，實驗值：763.2788[M+H]+.
化合物9j. 產率54%；m.p.125-127℃；tR-HPLC,3.72min(96.2%)；IR(KBr)ν cm-1：3339,3258,2966,1751,1666,1619,1539,1454,1401,1280,1258,1142,1085,1051,989,693,553；；1H NMR(CDCl3,400MHz)δ 8.38(s,1H,C7-H),
8.20(d,1H,J=8.8Hz,C12-H),7.94(d,1H,J=8.0Hz,C9-H),7.81(t,1H,C11-H),7.75(d,2H,J=8.0Hz,Ts-H),7.67(t,1H,C10-H),7.50(m,4H,Ts,Ph-H),7.37(s,1H,C14-H),7.18(d,2H,J=8.0Hz,Ph-H),7.00(s,1H,Ph-H),5.51(ABq,2H,J=17.6Hz,C17-H),5.26(s,2H,C5-H),4.66(m,1H,C23-H),4.40(s,2H,C30-H),2.37(s,3H,Ts-CH 3 ),1.90-2.23(m,3H,C18-H,L-isoleucine-CH(CH3)CH2CH3),1.14(m,2H,L-isoleucine-CH(CH3)CH 2CH3),0.78-0.86(m,9H,C19-H,L-isoleucine-CH(CH 3)CH2 CH 3)；13C NMR(100MHz,CDCl3)δ：168.2,166.6,166.0,157.2,152.2,148.9,146.7,144.0,133.0,131.0,130.6,130.4,129.8,129.0,128.4,128.3,128.2,128.1,126.2,142.2,140.3,120.9,95.5,67.4,50.1,42.2,39.7,37.4,31.8,24.9,21.4,15.0,11.3,7.4；C41H40N4O7S依HRMS的計算值：733.2690[M+H]+，實驗值：733.2669[M+H]+.
化合物9k. 產率52%；m.p.102-104℃；tR-HPLC,5.36min(96.4%)；IR(KBr)ν cm-1：3385,3262,2929,1750,1663,1611,1544,1451,1280,1246,1144,1048,812,757,693,552；1H NMR(CDCl3,400MHz)δ 8.39(s,1H,C7-H),8.22(d,1H,J=8.4Hz,C9-H),7.95(d,1H,J=8.0Hz,C12-H),7.82(m,3H,C11-H,Ts-H),7.67(t,1H,C10-H),7.36(s,1H,C14-H),7.21(d,2H,J=8.0Hz,Ts-H),7.17-7.15(m,3H,L-phenylalanine-Ph),7.10(d,2H,J=8.4Hz,-PhOCH3),6.99-7.02(m,2H,L-phenylalanine-Ph),6.89(d,2H,J=8.8Hz,-PhOCH3),5.50(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,
C5-H),4.91(m,1H,C23-H),4.23(s,2H,C30-H),3.78(s,3H,-PhOCH 3),3.12-3.06(m,2H,L-phenylalanine-CH 2 ),2.39(s,3H,Ts-CH 3),2.11-2.21(m,2H,C18-H),0.81(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ 169.0,166.7,166.4,159.4,157.2,152.2,148.9,146.2,144.3,134.8,131.5,131.0,129.8,129.4,129.1,128.6,128.4,128.2,128.1,127.2,126.4,124.0,142.2,140.3,120.5,114.9,95.9,67.2,55.3,54.9,50.1,38.7,36.6,32.0,21.4,7.4；C45H40N4O8S依HRMS的計算值：797.2640[M+H]+，實驗值：797.2661[M+H]+.
化合物9l. 產率35%；m.p.123-125℃；tR-HPLC,3.20min(100%)；IR(KBr)ν cm-1：3419,3269,2925,1751,1644,1601,1540,1401,1277,1236,1139,1087,1050,814,758,699,552；1H NMR(CDCl3,400MHz)δ 8.45(s,1H,C7-H),8.13(d,1H,J=8.4Hz,C9-H),7.97(d,1H,J=8.0Hz,C12-H),7.87(t,1H,C11-H),7.71(t,1H,C10-H),7.65(d,2H,J=8.4Hz,Ts-H),7.36(s,1H,C14-H),7.22(d,2H,J=8.0Hz,Ts-H),7.17-7.20(m,5H,L-phenylalanine-Ph),5.52(ABq,2H,J=17.2Hz,C17-H),5.26(s,2H,C5-H),4.91(m,1H,C-23H),4.11(m,2H,-CH 2OH),3.14-3.23(m,2H,L-phenylalanine-CH 2 ),2.39(s,3H,Ts-CH 3 ),2.11-2.21(m,2H,C18-H),0.91(m,3H,C19-H)；13C NMR(100MHz,CDCl3)δ：167.7,166.6,166.5,157.1,152.1,148.1,145.8,144.4,135.1,132.1,131.3,129.5,129.4,129.1,129.0,128.8,128.5,128.4,128.3,127.2,126.4,140.2,121.0,96.4,67.2,58.9,56.1,50.1,37.5,35.6,32.0,21.4,7.5；
C39H36N4O8S依HRMS的計算值：743.2146[M+Na]+，實驗值：743.2158[M+Na]+.
細胞株及細胞毒性檢定。在本文中所使用的人類腫瘤細胞株係A-549(肺癌)、MDA-MB-231(三陰性乳房癌)、DU-145(激素不敏感型前列腺癌)、KB(原始分離自表皮樣癌鼻咽)、KBvin(抗長春新鹼性KB亞株)及HCT116(結腸直腸腺癌)。這些細胞株係從Lineberger Comprehensive Cancer Center(UNC-CH)或從ATCC(Manassas，VA)獲得，除了KBvin外，其係Y.-C.Cheng教授(Yale University)慷慨饋贈的禮物。全部細胞株係於空氣中，在包含5% CO2的濕潤環境中，維持在包含2mM L-麩醯胺酸及25mM HEPES(HyClone)的RPMI-1640媒質中及檢定，以10%熱滅活的胎牛血清(HyClone)、100微克/毫升鏈黴素、100IU/毫升盤尼西林及0.25微克/毫升兩性黴素B(Cellgro)補充。化合物貯存溶液係製備成10mM在DMSO中及以培養媒質稀釋至最後DMSO濃度0.01%(v/v)，此濃度對細胞生長沒有影響。在37℃下，於96井板中，讓4-6×103細胞/井與多種濃度的測試化合物培養72小時。該化合物的抗增生活性係根據在NCI處所發展及證實的程序，藉由硫羅丹明(sulforhodamine)B檢定決定30，及與在72小時連續治療後之媒劑對照比較，其係以減少50%的細胞數目之IC50(μM)值表示出。每次檢定係以複製的樣品一式三份進行。
形態學觀察。在相位差顯微鏡下觀察培養細胞的形態學變化及以數位照相機(Nikon，日本)照相。
細胞凋亡評估。細胞凋亡係藉由膜聯蛋白V-FITC/碘化丙啶雙重染色工具組(BD Biosciences)偵測。A-549細胞係以9a治療24小時或48小時。藉由胰蛋白酶化採集細胞及以冰冷的PBS清洗。在室溫下，於黑暗中，以膜聯蛋白V-FITC及碘化丙啶標定細胞15分鐘。經標定的細胞係藉由FACSCalibur流式細胞儀(flow cytometer)(Becton Dickinson)分析。
細胞週期分析。A-549細胞係以冰冷的70% EtOH固定，接著碘化丙啶染色。樣品係藉由流式細胞儀分析用於細胞週期決定。以倍數體為基準(<2N為次-G1；2N為G1；在2N至4N間為S；4N為G2/M)來計算每個細胞週期時相(cell cycle phase)之總數，及藉由Student-t檢定統計評估(P<0.01)。
西方墨點分析。在包含蛋白酶抑制劑及磷酸酶抑制劑的PBS中採集細胞，及進行聲波處理。全部的細胞溶成物係藉由SDS-PAGE分離及轉移至Immobilon P薄膜(EMD Millipore)。該薄膜係以一級抗體(primary antibody)培養，接著以軛合蔊菜過氧化酶(HRP)的二級抗體(EMD Millipore)標定。使用化學發光基質工具組(EMD Millipore)來偵測膜結合的HRP，及藉由Luminsence影像分析器，LAS4000(Fuji Photo Film Co.，日本)具體化。
抗體。對凋亡蛋白酶-3、凋亡蛋白酶-8、凋亡蛋白酶-9、PARP、磷醯基-ATM(Ser1981)、ATM、磷醯基-ATR(Ser428)、磷醯基-Chk1(Ser345)、磷醯基-Chk2(Thr68)、Chk2、磷醯基-H2AX(Ser139)及磷醯基-p53(Ser15)的抗體係
從Cell Signaling Technology購買。對抗ATM、ATR、Chk1及PUMA的抗體係來自Santa Cruz Biotechnology。對抗TOPO I、TOPO II、TOPO II、p53、FADD、BAX、Bcl-xL及Bcl-2的抗體係來自BD Biosciences。對-肌動蛋白的抗體係從EMD Millipore購買。
在無細胞系統中的拓撲異構酶I活性檢定。讓一單位的重組人類拓撲異構酶I酵素(TopoGEN)，在37℃下，與媒劑、9a、1、3或SN-38在最後體積20微升的反應緩衝液(10mM Tris-HCl，pH 7.9，1mM EDTA，150mM NaCl，0.1% BSA，0.1mM精三胺，5%甘油)中預培養20分鐘，然後以250奈克超螺旋質體DNA培養20分鐘。該超螺旋、鬆解或鏈裂的DNA係藉由1%瓊脂糖凝膠以1×TAE(Tris-醋酸酯-EDTA)緩衝液分離。使用Gel Doc XR(Bio-Rad)對經溴化乙錠染色的瓊脂糖凝膠照相。
拓撲異構酶I活性檢定。根據製造者的用法說明，使用檢定工具組(TopoGEN)進行TOPO I活性測試。來自經9a治療的A-549細胞之核萃取物係在37℃下以超螺旋DNA(用於TOPO I)或鏈接的kDNA(用於TOPO II)培養30分鐘。該反應混合物係藉由1%瓊脂糖凝膠以1×TAE緩衝液分離。該凝膠係以溴化乙錠染色及使用Gel Doc XR(Bio-Rad)照相。
異種移植模型抗腫瘤檢定。讓五至六週大的母nu/nu老鼠(國家實驗動物中心(National Laboratory Animal Center)，台灣)在側腹中皮下接種2×106個人類結腸直腸腺癌HCT116細胞。當該經移植的腫瘤體積到達平均體積200立方
毫米時，將老鼠隨意劃分成四組(n=8)。治療方案係顯示在表2中。一天一次(QD)靜脈內給藥5或10毫克/公斤的媒劑對照及化合物9a 7天，然後一次一天腹膜內至結束。至於實驗對照組，將100毫克/公斤的化合物3一週一次(QWK)靜脈內給藥至結束。每3至4天測量該移植物的長度(L)及寬度(W)至結束，及該腫瘤體積係以LW2/2計算。結果係藉由Student-t檢定統計評估。此研究係由國立台灣大學(台北，台灣)的實驗動物照護及使用委員會(IACUC)認可，及根據該機構的指導方針進行。
活體內毒性之病理學評估。使用六十隻8週大的公BALB/c老鼠(國家實驗動物中心，台北，台灣)來評估單一劑量毒性。將老鼠隨意分成六組(n=10)及在第0天時接受0(媒劑)、30、100、200或300毫克/公斤的9a單一腹膜內注射。一組未治療作為正常對照。每三天測量體重十五天。在實驗時期結束時，全部動物皆藉由CO2安樂死及對來自肝、肺、腎及脾的組織稱重(資料無顯示)。該等組織係以10%福馬林固定及埋入石蠟中。製備3-5微米厚的切片用於組織病理學檢驗。根據由Shackelford等人所描述的指導方針，對經蘇木紫及伊紅(H&E)染色的石蠟切片進行組織病理學評估36，及根據症狀的病灶分級。病灶程度依嚴重性分成一至五的等級，如下；[沒有明顯的事物，1=最小(<1%)，2=輕微(1-25%)，3=中等(26-50%)，4=中度嚴重(51-75%)，5=嚴重(76-100%)]。此顯示出統計顯著性結果(P<0.05)。此研究係由中國醫藥大學(台中，台灣)的實驗動物照護及使用委員會(IACUC)認可，及根
據該機構的指導方針進行。
ATM，毛細血管擴張性失調突變(ataxia telangiectasia mutated)；ATR，毛細血管擴張及Rad3相關性失調(ataxia telangiectasia and rad3-related)；Chk，檢驗點激酶；CPT，喜樹鹼；DIPC，N,N’-二異丙基碳二醯亞胺；DMAP，4-二甲基胺基吡啶；FADD，具有死亡區段之Fas相關蛋白質；PUMA，細胞凋亡的p53調升調節劑；TFA，三氟醋酸；Topo，拓撲異構酶。
化合物10a-10t係使用類似於在具體實例I中所描述的那些程序合成及鑑別，其係顯示在表3中。
將三乙基胺(1.2毫莫耳)慢慢加入至多種TFA鹽8(0.5毫莫耳)在CH2Cl2(35毫升)中的懸浮液，及攪拌此混合物10分鐘，當獲得一透明溶液時。在N2環境中，於室溫下將炔(0.5毫w莫耳)、磺基疊氮(0.6毫莫耳)及CuI(0.05毫莫耳)加入此反應混合物。在該反應完成後，如藉由TLC監視，該反應混合物係藉由加入CH2Cl2(4毫升)及NH4Cl水溶液(6毫升)稀釋。攪拌該混合物額外30分鐘及分離成二層。以CH2Cl2
萃取(3毫升×3)水層。在MgSO4上乾燥該結合的有機層，過濾及在真空中濃縮。該粗產物殘餘物係藉由快速管柱層析法與適當的沖提溶劑系統純化。
化合物10a-10t對抗四種人類腫瘤細胞株的試管內細胞毒性係顯示在表4中。
化合物10a. 產率70%；橘黃色固體；mp133-134℃；IR(KBr)ν(cm-1)：3432,2978,2939,1753,1664,1618,1560,1449,1402,1385(NO．),1273,1147,1094,881,761,669,616,556；C41H46N5O9S理論計算值：C,62.74；H,5.91；N,8.92.實驗值：C,62.70；H,6.01；N,8.87；EPR：g0=2.0064,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：785.3[M+H]+.
化合物10b. 產率67%；橘黃色固體；mp118-121℃；IR(KBr)ν(cm-1)：3433,2977,2938,1752,1664,1618,1545,1458,1403,1384(NO．),1273,1145,1090,881,787,724,616,555；C42H48N5O9S理論計算值：C,63.14；H,6.06；N,8.77.實驗值：C,63.10；H,6.01；N,8.90；EPR：g0=2.0060,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：800.2
[M+2H]+.
化合物10c. 產率71%；橘黃色固體；mp128-130℃；IR(KBr)ν(cm-1)：3448,2975,2930,2873,1751,1666,1618,1561,1546,1439,1402,1385(NO．),1272,1145,1091,881,670,616,555；C44H52N5O9S理論計算值：C,63.90；H,6.34；N,8.47.實驗值：C,64.03；H,6.31；N,8.56；EPR：g0=2.0061,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：828.3[M+2H]+.
化合物10d. 產率70%；橘黃色固體；mp125-127℃；IR(KBr)ν(cm-1)：3448,2974,2929,1752,1655,1618,1560,1508,1402,1385(NO．),1272,1122,881,788,670,617,474；C35H42N5O9S理論計算值：C,59.31；H,5.97；N,9.88.實驗值：C,59.43；H,6.01；N,8.79；EPR：g0=2.0066,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：731.3[M+Na]+.
化合物10e. 產率64%；橘黃色固體；mp124-126℃；IR(KBr)ν(cm-1)：3431,2974,2929,1753,1655,1618,1561,1508,1439,1403,1384(NO．),1270,1233,1118,881,787,758,616,475；C36H44N5O9S理論計算值：C,59.82；H,6.14；N,9.69.實驗值：C,59.73；H,6.08；N,9.58；EPR：g0=2.0064,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：745.4[M+Na]+.
化合物10f. 產率66%；橘黃色固體；mp123-125℃；IR(KBr)ν(cm-1)：3423,2973,2926,2870,1758,
1663,1618,1561,1458,1404,1384(NO．),1267,1234,1181,1119,881,788,763,724,669,616；C38H48N5O9S理論計算值：C,60.78；H,6.44；N,9.33.實驗值：C,60.89；H,6.38；N,9.50；EPR：g0=2.0060,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESIm/z：773.4[M+Na]+.
化合物10g. 產率68%；橘黃色固體；mp142-144℃；IR(KBr)ν(cm-1)：3423,2975,2931,1753,1664,1618,1560,1499,1458,1403,1384(NO．),1257,1146,1094,881,854,805,762,724,696,614,555；C41H46N5O10S理論計算值：C,61.49；H,5.79；N,8.74.實驗值：C,61.54；H,5.86；N,8.67；EPR：g0=2.0062,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：823.2[M+Na]+.
化合物10h. 產率73%；橘黃色固體；mp144-146℃；IR(KBr)ν(cm-1)：3423,2975,2934,1753,1666,1618,1561,1508,1458,1402,1385(NO．),1272,1234,1149,1095,881,762,726,618,483；C40H43ClN5O9S理論計算值：C,59.66；H,5.38；N,8.70.實驗值：C,59.70；H,5.45；N,8.57；EPR：g0=2.0064,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：806.3[M+2H]+.
化合物10i. 產率64%；橘黃色固體；mp105-107℃；IR(KBr)ν(cm-1)：3422,2975,2930,2871,1753,1663,1593,1560,1496,1458,1403,1383(NO．),1272,1236,1147,1091,1050,880,839,764,669,616,555；C40H43FN5O9S理論計算值：C,60.90；H,5.49；N,8.88.實驗值：C,61.01；H,
5.55；N,8.49；EPR：g0=2.0066,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：790.3[M+2H]+.
化合物10j. 產率68%；橘黃色固體；mp135-137℃；IR(KBr)ν(cm-1)：3393,2973,2901,1757,1663,1606,1560,1529,1450,1404,1384(NO．),1351,1223,1150,1081,1050,880,747,617,464；C40H43N6O11S理論計算值：C,58.89；H,5.31；N,10.30.實驗值：C,58.94；H,5.45；N,10.25；EPR：g0=2.0060,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：817.4[M+2H]+.
化合物10k. 產率62%；橘黃色固體；mp120-122℃；IR(KBr)ν(cm-1)：3385,2973,2900,1750,1663,1618,1549,1452,1404,1384(NO．),1272,1234,1146,1087,1050,880,814,763,689,618,556；C45H54N5O9S理論計算值：C,64.27；H,6.47；N,8.33.實驗值：C,64.38；H,6.56；N,8.21；EPR：g0=2.0062,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：842.4[M+2H]+.
化合物10l. 產率70%；橘黃色固體；mp122-124℃；IR(KBr)ν(cm-1)：3401,2973,2935,2873,1751,1664,1604,1545,1458,1403,1384(NO．),1273,1147,1091,1051,881,815,669,617,556；C45H54N5O9S理論計算值：C,64.27；H,6.47；N,8.33.實驗值：C,64.38；H,6.56；N,8.21；EPR：g0=2.0064,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：842.4[M+2H]+.
化合物10m. 產率68%；橘黃色固體；
mp112-114℃；IR(KBr)ν(cm-1)：3402,2974,2901,1751,1655,1618,1560,1544,1450,1405,1384(NO．),1250,1079,1066,1050,881,701,617；C48H52N5O9S理論計算值：C,65.89；H,5.99；N,8.00.實驗值：C,65.98；H,6.12；N,8.06；EPR：g0=2.0066,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：876.4[M+2H]+.
化合物10n. 產率59%；橘黃色固體；mp141-143℃；IR(KBr)ν(cm-1)：3411,2974,2932,1754,1662,1604,1560,1458,1403,1384(NO．),1272,1236,1127,1082,1050,880,787,724,688,619,555,480；C44H46N5O9S理論計算值：C,64.37；H,5.65；N,8.53.實驗值：C,64.30；H,5.54；N,8.46；EPR：g0=2.0062,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：822.4[M+2H]+.
化合物10o. 產率67%；橘黃色固體；mp136-138℃；IR(KBr)ν(cm-1)：3423,2975,2938,1753,1663,1617,1560,1458,1404,1384(NO．),1292,1234,1143,1093,1015,881,762,724,669,618,592；C38H42N5O9S2理論計算值：C,58.75；H,5.45；N,9.01.實驗值：C,58.65；H,5.38；N,9.21；EPR：g0=2.0066,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：878.3[M+2H]+.
化合物10p.產率75%；橘黃色固體；mp105-107℃；IR(KBr)ν(cm-1)：3423,2974,2928,1756,1663,1601,1560,1457,1403,1384(NO．),1273,1236,1177,1147,1094,1050,920,881,818,763,695,615,556,480；
C42H48N5O9S理論計算值：C,63.14；H,6.06；N,8.77.實驗值：C,63.04；H,6.19；N,8.92；EPR：g0=2.0060,An=14.62Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：800.4[M+2H]+.
化合物10q. 產率65%；淡黃色固體；mp121-123℃；IR(KBr)ν(cm-1)：3415,2973,2931,2871,1757,1663,1603,1561,1442,1402,1384(NO．),1256,1190,1120,1084,1049,977,881,787,724,613,562,475；C35H40N5O9S理論計算值：C,59.48；H,5.70；N,9.91.實驗值：C,59.56；H,5.63；N,10.02；EPR：g0=2.0058,An=14.76Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：729.3[M+Na]+；
化合物10r. 產率61%；淡黃色固體；mp110-112℃；IR(KBr)ν(cm-1)：3422,2974,2929,1752,1655,1603,1560,1458,1439,1384(NO．),1273,1147,1093,1050,881,724,695,616,556；C41H44N5O9S理論計算值：C,62.90；H,5.66；N,8.95.實驗值：C,63.00；H,5.53；N,9.01；EPR：g0=2.0055,An=14.76Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：805.4[M+Na]+.
化合物10s. 產率70%；淡黃色固體；mp120-122℃；IR(KBr)ν(cm-1)：3415,2974,2929,1756,1664,1598,1560,1499,1458,1403,1384(NO．),1258,1146,1094,1051,881,836,805,725,697,614,567；C41H44N5O10S理論計算值：C,61.64；H,5.55；N,8.77.實驗值：C,61.81；H,5.42；N,8.85；EPR：g0=2.0058,An=14.76Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：800.3[M+2H]+.
化合物10t. 產率69%；淡黃色固體；mp103-105℃；IR(KBr)ν(cm-1)：3423,2974,2927,1753,1663,1592,1560,1495,1458,1403,1384(NO．),1279,1234,1186,1148,1091,880,839,763,724,699,613,554,481；C40H41FN5O9S理論計算值：C,61.06；H,5.25；N,8.90.實驗值：C,61.21；H,5.15；N,9.02；EPR：g0=2.0055,An=14.76Gs(三重峰於1×10-4M,DMF)；MS-ESI m/z：809.4[M+Na]+.
使用類似於在具體實例I中所描述的那些程序合成及鑑別更多種衍生物，其係顯示在表5中。
在表5中的數種化合物對抗四種人類腫瘤細胞株之試管內細胞毒性係顯示在表6中。
化合物Wcpt-37. 產率50%；1H NMR(DMSO-d 6 ,400MHz)δ：8.88-9.00(m,1H,NH),8.00(d,1H,J=10.0Hz,C12-H),7.54(d,2H,J=8.0Hz,Ph-H),7.40(m,2H,C11-H,C9-H),7.18(d,2H,J=8.4Hz,Ph-H),7.03(d,2H,J=7.6Hz,Ph-H),7.00(s,1H,C14-H),6.77(d,1H,J=8.4Hz,Ph-H),5.76(s,1H,C10-OH),5.50(s,2H,C17-H),5.29(s,2H,C5-H),4.35(dd,1H,J=5.6,18.0Hz,C23-H),4.24(dd,1H,J=5.6,17.2Hz,C23-H),4.01(s,2H,C30-H),3.66(s,3H,p-CH3OPh),3.11(m,2H,C7-CH 2 CH3),2.21(s,3H,Ts-CH 3),2.09-2.10(m,2H,C18-H),1.29(d,3H,J=7.2Hz,C7-CH2 CH 3 ),0.84(t,3H,J=7.2Hz,C19-H)；MS-ESI m/z：751.5[M+H]+.
化合物Wcpt-39. 產率51%；1H NMR(DMSO-d 6 ,400MHz)δ：8.93(s,1H,NH),8.14(d,1H,J=9.2Hz,C12-H),7.98(s,1H,
C9-H),7.65(d,1H,J=9.2Hz,C11-H),7.51(d,2H,J=8.0Hz,Ph-H),7.18(d,2H,J=8.4Hz,Ph-H),7.07(s,1H,C14-H),6.98(d,2H,J=8.4Hz,Ph-H),6.76(d,2H,J=8.4Hz,Ph-H),5.52(s,2H,C17-H),5.34(s,2H,C5-H),4.19-4.39(m,4H,C7-CH 2 ,C23-H),4.00(s,2H,C30-H),3.65(s,3H,p-CH3OPh-H),3.08-3.20(m,4H,C1’-H,C1”-H),2.92(t,1H,J=12.4Hz,C3’-H),2.74(m,6H,C7-CH 2 CH3,C4’-H,4”-H),2.40(s,3H,Ts-CH 3 ),2.06-2.24(m,7H,C6’-H,C5’-H,C5”-H,C18-H),2.05(m,4H,C4’-H,C4”-H),1.71(t,3H,J=7.2Hz,C7-CH2 CH 3 ),0.84(t,3H,J=7.2Hz,C19-H)；MS-ESI m/z：945.2[M+H]+.
化合物#9 產率42%；1H NMR(DMSO-d 6 ,400MHz)δ 8.92(t,1H,J=5.6Hz,NH),8.75(s,1H,C7-H),7.95(d,1H,J=9.2Hz,C12-H),7.50(d,2H,J=8.0Hz,Ph-H),7.44(d,1H,J=9.2Hz,C11-H),7.18(d,2H,J=8.8Hz,Ph-H),6.97-7.03(m,3H,C14-H,Ph-H),6.77(d,2H,J=8.4Hz,Ph-H),5.50(s,2H,C17-H),5.23(s,2H,C5-H),4.20-4.39(m,2H,C23),4.04(s,2H,C30-H),4.00(s,2H,9-CH 2 -),3.68(s,3H,-PhOCH 3 ),2.67-2.90(m,8H,
piperazine-H),2.37(s,3H,piperazine-CH3),2.20(s,3H,Ts-CH3),2.10-2.13(m,2H,C18-H),0.84(m,3H,C19-H)；MS-ESI m/z：835.3[M+H]+.
化合物#10. 產率64%；1H NMR(DMSO-d 6 ,400MHz)δ 8.91(t,1H,J=5.6Hz,NH),8.69(s,1H,C7-H),8.10-8.15(m,2H,C9-H,C12-H),7.83-7.84(m,1H,C11-H),7.71(t,1H,J=7.6Hz,C10-H),7.49(d,2H,J=8.0Hz,Ph-H),7.17(d,2H,J=8.4Hz,Ph-H),7.10(s,1H,C14-H),7.00-7.03(m,2H,Ph-H),6.76(d,2H,J=8.8Hz,Ph-H),5.41-5.76(m,3H,C17-H,C5-H),4.21-4.39(m,2H,C23),4.00(s,2H,C30-H),3.67(s,3H,-PhOCH 3 ),2.20(s,3H,Ts-CH3),2.11-2.13(m,2H,C18-H),1.83-1.87(m,3H,5-CH 3 ),0.85(m,3H,C19-H)；MS-ESI m/z：743.2[M+Na]+.
化合物#11. 產率62%；1H NMR(DMSO-d 6 ,400MHz)δ 9.10(s,0.5H,NH),8.90(s,0.5H,NH),8.69(s,1H,C7-H),8.12-8.14(m,2H,C9-H,C12-H),7.85(t,1H,J=7.6Hz,C11-H),7.71(t,1H,J=7.2Hz,C10-H),7.48-7.52(m,2H,Ph-H),7.17-7.31(m,2H,Ph-H),7.12(s,1H,C14-H),7.02-7.06(m,3H,Ph-H),6.76(d,1H,J=8.4Hz,Ph-H),5.52(s,2H,C17-H),5.29(s,2H,C5-H),4.21-4.39(m,2H,C23),4.00(s,2H,C30-H),2.20(s,3H,Ts-CH3),2.11-2.13(m,2H,C18-H),0.85(m,3H,C19-H)；MS-ESI m/z：695.2[M+H]+.
化合物#13. 產率56%；1H NMR(DMSO-d 6 ,400MHz)δ：8.88(t,1H,J=5.8Hz,NH),8.28(d,1H,J=8.2Hz,C9-H),8.13(d,1H,J=7.8Hz,C12-H),7.83(t,1H,J=7.2Hz,C11-H),7.71(t,1H,J=7.2Hz,C10-H),7.52(d,2H,J=8.2Hz,Ph-H),7.18(d,2H,J=8.8Hz,Ph-H),7.08(s,1H,C14-H),7.01(d,2H,J=8.0Hz,Ph-H),6.76(d,1H,J=8.8Hz,Ph-H),5.51(s,2H,C17-H),5.32(s,2H,C5-H),4.35(dd,1H,J=6.0,18.0Hz,C23-H),4.28(dd,1H,J=6.0,18.0Hz,C23-H),4.00(s,2H,C30-H),3.64(s,3H,p-CH 3 OPh),3.22(q,2H,J=7.4Hz,C7-CH 2 CH3),2.19(s,3H,Ts-CH 3),2.10-2.12(m,2H,C18-H),1.30(d,3H,J=7.6Hz,
C7-CH2 CH 3 ),0.84(t,3H,J=7.2Hz,C19-H)；MS-ESI m/z：735.8[M+H]+.
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Claims (15)
- 一種具有下列結構的化合物，
- 如請求項1之化合物，其中R3、R4、R5、R6及R7全部係H、n係0、m係1及X係O。
- 如請求項2之化合物，其中R9係C1-C6烷基、C1-C3烷基 苯基、C1-C3烷氧基苯基、氟苯基、氯苯基或
- 如請求項3之化合物，其中R2係羥基C1-C6烷基、苯基、C1-C3烷氧基苯基、或(CH2)j-O-(CH2)i-R11，其中j係1；i係 0或1；及R11係或，其中R8、R10、R12 及R13全部係甲基。
- 如請求項4之化合物，其中R1係H、C1-C6烷基、或苯基甲基。
- 如請求項5之化合物，其中R2係對-甲氧基苯基。
- 如請求項5之化合物，其中R2係(CH2)j-O-(CH2)i-R11，其 中j係1；i係0或1；及R11係或，其中 R8、R10、R12及R13全部係甲基。
- 如請求項1之化合物，其中R2係對-甲氧基苯基或對-氟苯基、R1及R4二者係H、R9係對-甲基苯基、n係0、m係1及X係O。
- 如請求項8之化合物，其中R5係CH3CH2、R6係H或OH、R7係H、R2係對-甲氧基苯基、及R3係H。
- 如請求項8之化合物，其中R5係CH3CH2、R6係H、R7 係H、R2係對-甲氧基苯基、及R3係
- 如請求項8之化合物，其中R5及R7二者係H、R6係OH、 R2係對-甲氧基苯基、及R3係，其中R8係甲基。
- 如請求項8之化合物，其中R3、R5及R6全部係H、R7係甲基、R2係對-甲氧基苯基。
- 如請求項8之化合物，其中R3、R5、R6及R7全部係H、R2係對-氟苯基。
- 一種如請求項1至13之任一項的化合物之用途，其係使用來製造用於治療癌的藥劑。
- 如請求項14之用途，其中該癌係結腸癌、鼻咽癌、肺癌、乳房癌、前列腺癌或卵巢癌。
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| EP (1) | EP3049419B1 (zh) |
| JP (1) | JP6182720B2 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105884789A (zh) * | 2016-05-18 | 2016-08-24 | 兰州大学 | 10-氟喜树碱类衍生物及其制备方法及用途 |
| CN111689978A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰胺类化合物及其制备方法和用途 |
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| CN111689977A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰脲类化合物及其制备方法和用途 |
| CN111689979A (zh) * | 2019-03-12 | 2020-09-22 | 兰州大学 | 一种9-位哌嗪磺酰胺-10-羟基喜树碱类化合物及其制备方法和在抗肿瘤中的用途 |
| CN117279664A (zh) | 2021-04-10 | 2023-12-22 | 普方生物制药美国公司 | Folr1结合剂、其偶联物及其使用方法 |
| AU2022262644A1 (en) | 2021-04-23 | 2023-11-09 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
| TW202320857A (zh) | 2021-07-06 | 2023-06-01 | 美商普方生物製藥美國公司 | 連接子、藥物連接子及其結合物及其使用方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5646159A (en) * | 1994-07-20 | 1997-07-08 | Research Triangle Institute | Water-soluble esters of camptothecin compounds |
| ES2529060T3 (es) | 2008-11-24 | 2015-02-16 | Cedars-Sinai Medical Center | Derivados antioxidantes de la camptotecina y nanoesferas antineoplásicas antioxidantes de los mismos |
| US8575188B2 (en) * | 2009-06-17 | 2013-11-05 | Threshold Pharmaceuticals, Inc. | Camptothecin derivatives |
| CN102086208B (zh) * | 2010-12-10 | 2013-01-02 | 兰州大学 | 4β-鬼臼毒素脒类化合物及其制备方法和用途 |
| KR101688898B1 (ko) * | 2011-11-03 | 2016-12-22 | 타이완 리포솜 캄퍼니 리미티드 | 소수성 캄프토테신 유도체의 약제 조성물 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884789A (zh) * | 2016-05-18 | 2016-08-24 | 兰州大学 | 10-氟喜树碱类衍生物及其制备方法及用途 |
| CN111689978A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰胺类化合物及其制备方法和用途 |
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| JP2016531877A (ja) | 2016-10-13 |
| JP6182720B2 (ja) | 2017-08-23 |
| US20160229862A1 (en) | 2016-08-11 |
| EP3049419B1 (en) | 2017-11-08 |
| US9718835B2 (en) | 2017-08-01 |
| WO2015048365A1 (en) | 2015-04-02 |
| EP3049419A1 (en) | 2016-08-03 |
| KR20160055925A (ko) | 2016-05-18 |
| KR101844802B1 (ko) | 2018-04-03 |
| EP3049419A4 (en) | 2017-02-22 |
| TWI526446B (zh) | 2016-03-21 |
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