臺灣博碩士論文加值系統

本論文主旨為設計與合成一系列喹唑啉(quinazoline)衍生物作為潛能抗癌藥物。已有報導嘧啶(pyrimidine)的衍生物PNU112455A和嘌呤(purine)的衍生物NU2058對CDK2 (cyclin dependent kinases 2)有良好的抑制效果，從PNU112455和NU2058和CDK2的結合模式上推斷，PNU112455A上的苯胺基團和NU2058上的cyclohexanemethylene基團是決定控制活性強弱的重要關鍵，有鑑於此，我們設計一系列quinazoline衍生物，其中第2位置接上含不同取代基之苯胺基團以及第4位置接上cyclohexylamine或cyclohexanemethylamine基團，藉以達到CDK2的良好抑制效果。將2,4-quinazolinedione (1)以POCl3氯化之後形成2,4-dichloroquinazoline (2)，然後進行取代反應，在第4位置分別接上cyclohexylamino或cyclohexanemethylamino兩種基團，最後再進行一次取代反應，在第2位置則接上具有不同取代基的苯胺，分別得到兩個系列標的化合物2-anilino-4-cyclohexylaminoquinazoline 4a – i 和2-anilino-4-cyclohexanemethylaminoquinazoline 6a - h。合成的標的化合物均採MTT篩選方法，分別對胃癌細胞株AGS、肺癌細胞株A549和CL1-5、肝癌細胞株HepG2、大腸直腸癌細胞株HT-29和前列腺癌細胞株PC-3進行體外細胞毒性測試。結果發現苯胺上有鹵素取代的化合物4c、4e、4f、4h、6b - 6f、6h都有顯著的抑制活性，其中又以間位為氯取代和對位為溴取代的化合物6b及6d的效果最好，GI50分別可以達到0.1及0.08 μM。另外，分析6b對HepG2細胞週期之影響，發現6b在48小時後有Sub-G1出現，引發細胞凋亡。證明這系列的化合物具有極高發展成為抗癌藥物的潛力。

This thesis is aimed to design and synthesize a series of quinazloine derivatives as potential antitumor agents. The pyrimidine derivative, PNU112455A and purine derivative NU2058 have been demonstrated to have great inhibitory activity against CDK2 (cyclin dependent kinase 2). Based on the binding modes of PNU112455 and NU2058 with CDK2, the aniline group on PNU112455 and cyclohexanemethylene group on NU2058 play essential roles in enhancing CDK2 inhibitory activity. Accordingly, we designed a series of quinazoline derivatives in which the second and four positions were introduced by substituted anilino and cyclohexylamino or cyclohexanemethylamino groups, respectively, in order to achieve good inhibitory activity against CDK2. 2,4-Quinazolinedione (1) underwent chlorination with POCl3 to afford 2,3-dichloroquinazoline (2), and nucleophilic addition was proceeded to introduce either cyclohexylamino or cyclohexanemethylamino group at the four position. Then, a second nucleophilic addition with different substituted anilines to provide the two target compounds 2-anilino-4-cyclohexylaminoquinazoline 4a – i and 2-anilino-4-cyclohexanemethylaminoquinazoline 6a – h. All synthesized compounds were subjected to MTT assay to test the in vitro cytotoxicity against stomach cancer cell line AGS, lung cancer cell lines A549 and CL1-5, liver cancer cell line HepG2, colon cancer cell line HT-29, and prostate cancer cell line PC-3. The results showed that halogenated anilino substituted compounds 4c、4e、4f、4h、6b - 6f、6h possessed good inhibitory activity. Among them, 6b and 6d have the highest antitumor activity with GI50 values of 0.1 and 0.08 M, respectively. Analysis of the cell cycle of HepG2 treated with 6b, it was found that subG1 peak appeared after 48 hours, indicative of an apoptosis occurring. The in vitro cytotoxicity demonstrated that this series of compounds have great potentials as anticancer drugs.

目錄
第一章 緒論 1
第二章 實驗設計 15
第三章 結果與討論 18
3.1 標的化合物的合成 18
3.1.1 2,4-Quinazolinedione (1)的合成 18
3.1.2 2,4-Dichloroquinazoline (2)的合成 19
3.1.3 2-Chloro-4-cyclohexylaminoquinazoline (3)的合成 21
3.1.4 2-Anilino-4-cyclohexylaminoquinazoline衍生物4a - i的合成 22
3.1.5 2-Chloro-4-cyclohexanemethylaminoquinazoline (5)的合成 23
3.1.6 2-Anilino-4-cyclohexanemethylaminoquinazoline衍生物6a - h的合成 24
3.2 體外生物活性測試 25
3.3 流式細胞儀分析 28
第四章 結論 30
第五章 實驗部分 31
5.1 檢驗方法與實驗儀器 31
5.2 試藥、溶劑 31
5.3 合成步驟 31
第六章 參考資料 45

附錄
1H NMR spectrum of 2,4-Quinazolinedione (1)………………………A-1
13C NMR spectrum of 2,4-Quinazolinedione (1)………………………A-2
1H NMR spectrum of 2,4-Dichloroquinazoline (2)……………………A-3
13C NMR spectrum of 2,4-Dichloroquinazoline (2)……………………A-4
1H NMR spectrum of 2-Chloro-4-cyclohexylaminoquinazoline (3)……A-5
13C NMR spectrum of 2-Chloro-4-cyclohexylaminoquinazoline (3)……A-6
1H NMR spectrum of 2-Anilino-4-cyclohexylaminoquinazoline (4a)…A-7
13C NMR spectrum of 2-Anilino-4-cyclohexylaminoquinazoline (4a)…A-8
GC-MS spectrum of 2-Anilino-4-cyclohexylaminoquinazoline (4a)…A-9
1H NMR spectrum of 2-(3-Chloroanilino)-4-cyclohexylaminoquinazoline (4b)…………………………………………………………………A-10
13C NMR spectrum of 2-(3-Chloroanilino)-4-cyclohexylaminoquinazoline (4b)…………………………………………………………………A-11
GC-MS spectrum of 2-(3-Chloroanilino)-4-cyclohexylaminoquinazoline (4b)…………………………………………………………………A-12
1H NMR spectrum of 4-Cyclohexylamino-2-(3-fluoroanilino)quinazoline (4c)…………………………………………………………………A-13
13C NMR spectrum of 4-Cyclohexylamino-2-(3-fluoroanilino)quinazoline (4c)…………………………………………………………………A-14
GC-MS spectrum of 4-Cyclohexylamino-2-(3-fluoroanilino)quinazoline (4c)…………………………………………………………………A-15
1H NMR spectrum of 4-Cyclohexylamino-2-(3-nitroanilino)quinazoline (4d)…………………………………………………………………A-16
13C NMR spectrum of 4-Cyclohexylamino-2-(3-nitroanilino)quinazoline (4d)…………………………………………………………………A-17
1H NMR spectrum of 2-(4-Chloroanilino)-4-cyclohexylaminoquinazoline (4e)…………………………………………………………………A-18
13C NMR spectrum of 2-(4-Chloroanilino)-4-cyclohexylaminoquinazoline (4e)…………………………………………………………………A-19
GC-MS spectrum of 2-(4-Chloroanilino)-4-cyclohexylaminoquinazoline (4e)…………………………………………………………………A-20
1H NMR spectrum of 2-(4-Bromoanilino)-4-cyclohexylamino-quinazoline (4f)…………………………………………………………………A-21
13C NMR spectrum of 2-(4-Bromoanilino)-4-cyclohexylamino-quinazoline (4f)…………………………………………………………………A-22
GC-MS spectrum of 2-(4-Bromoanilino)-4-cyclohexylamino-quinazoline (4f)…………………………………………………………………A-23
1H NMR spectrum of 4-Cyclohexylamino-2-(4-methoxyanilino)quinazoline (4g)………………………………………………………………A-24
13C NMR spectrum of 4-Cyclohexylamino-2-(4-methoxyanilino)quinazoline (4g)…………………………………………………………………A-25
GC-MS spectrum of 4-Cyclohexylamino-2-(4-methoxyanilino)quinazoline (4g)………………………………………………………………….A-26
1H NMR spectrum of 2-(4-Aminoanilino)-4-cyclohexylaminoquinazoline (4h)…………………………………………………………………A-27
13C NMR spectrum of 2-(4-Aminoanilino)-4-cyclohexylaminoquinazoline (4h)………………………………………………………………A-28
1H NMR spectrum of 4-Cyclohexylamino-2-(3,4,5-trimethoxyanilino)
quinazoline (4i)…………………………………………………A-29
13C NMR spectrum of 4-Cyclohexylamino-2-(3,4,5-trimethoxyanilino)
quinazoline (4i)………..…………………………………………A-30
GC-MS spectrum of 4-Cyclohexylamino-2-(3,4,5-trimethoxyanilino)
quinazoline (4i)…………………………………………………A-31
1H NMR spectrum of 2-Chloro-4-cyclohexanemethylaminoquinazoline (5)…………………………………………………A-32
13C NMR spectrum of 2-Chloro-4-cyclohexanemethylaminoquinazoline (5)……………………………………………………A-33
1H NMR spectrum of 2-Anilino-4-cyclohexanemethylaminoquinazoline (6a)………………………………………………………………A-34
13C NMR spectrum of 2-Anilino-4-cyclohexanemethylaminoquinazoline (6a)…………………………………………………………A-35
GC-MS spectrum of 2-Anilino-4-cyclohexanemethylaminoquinazoline (6a)……………………………………………………A-36
1H NMR spectrum of 2-(3-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6b)…………………………………………………A-37
13C NMR spectrum of 2-(3-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6b)……………………………………………A-38
GC-MS spectrum of 2-(3-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6b)…………………………………A-39
1H NMR spectrum of 4-Cyclohexanemethylamino-2-(3-fluoroanilino)-
quinazoline (6c)…………………………………………………A-40
13C NMR spectrum of 4-Cyclohexanemethylamino-2-(3-fluoroanilino)-
quinazoline (6c)……………………………………………A-41
GC-MS spectrum of 4-Cyclohexanemethylamino-2-(3-fluoroanilino)-
quinazoline (6c)……………………………………A-42
1H NMR spectrum of 2-(4-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6d)…………………………………………………A-43
13C NMR spectrum of 2-(4-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6d)……………………………………………A-44
GC-MS spectrum of 2-(4-Chloroanilino)-4-cyclohexanemethylamino-
quinazoline (6d)……………………………………A-45
1H NMR spectrum of 2-(4-Bromoanilino)-4-cyclohexanemethylamino-
quinazoline (6e)…………………………………………………A-46
13C NMR spectrum of 2-(4-Bromoanilino)-4-cyclohexanemethylamino-
quinazoline (6e)……………………………………………A-47
GC-MS spectrum of 2-(4-Bromoanilino)-4-cyclohexanemethylamino-
quinazoline (6e)……………………………………A-48
1H NMR spectrum of 4-Cyclohexanemethylamino-2-(4-methoxyanilino)-
quinazoline (6f)…………………………………………………A-49
13C NMR spectrum of 4-Cyclohexanemethylamino-2-(4-methoxyanilino)-
quinazoline (6f)……………………………………………A-50
GC-MS spectrum of 4-Cyclohexanemethylamino-2-(4-methoxyanilino)-
quinazoline (6f)……………………………………A-51
1H NMR spectrum of 2-(4-Aminoanilino)-4-cyclohexanemethylamino-
quinazoline (6g)…………………………………………………A-52
13C NMR spectrum of 2-(4-Aminoanilino)-4-cyclohexanemethylamino-
quinazoline (6g)……………………………………………A-53
1H NMR spectrum of 2-(4-Hydroxyanilino)-4-(cyclohexanemethylamino)-
quinazoline (6h)…………………………………………………A-54
13C NMR spectrum of 2-(4-Hydroxyanilino)-4-(cyclohexanemethylamino)-
quinazoline (6h)……………………………………………A-55

1 Information receved from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
2 Hartwell, L. H.; Weinert, T. A. Checkpoints: Controls that Ensure the Order of Cell Cycle Events. Science 1989, 246, 629-34.
3 Gavin, B.; La Thangue, N. B. The Cell Cycle and Drug Discovery: the Promising and the Hope. Drug Disc. Today. 1999, 4, 455-464.
4 Bramson, H. N.; Corona, J.; Davis, S. T.; Dickerson, S. H.; Edelstein, M.; Frye, S. V.; Gampe, R. T.; Jr.; Haais, P. A.; Hassell, A.; Holmes, W. D.; Hunter, R. N.; Lackey, K. E.; Lovejoy, B.; Luzzio, M. J; Montana, V.; Rocque, W. J.; Rusnak, D.; Shewchuk, L.; Veal, J. M.; Walker, D. H.; Kuyper, L. F. Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2): Design, Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis. J. Med. Chem. 2001, 44, 4339-4358.
5 Malumbres, M.; Barbacid, M. To Cycle or Not to Cycle: A Critical Decision in Cancer. Nature Rev. Cancer 2001, 1, 222-231.
6 Nabel, E. G. CDKs and CKIs : Molecular Targets for Tissue Remodelling. Nature Rev. Drug Discov. 2002, 1, 587-598.
7 Dubravka, D.; Scott, D. W. Regulation of the G1 Phase of the Mammalian Cell Cycle. Cell Res. 2000, 10, 1-16.
8 LaBaer, J.; Garrett, M. D.; Stevenson, L. F.; Slingerland, J. M.; Sandhu, C.; Chou, H. S.; Fattaey, A.; Harlow E. New Functional Activities for the p21 Family of CDK Inhibitors. Genes Dev. 1997, 7, 847-62
9 Havlıcek, L.; Hanus, J.; Vesely, J.; Leclerc, R.; Meijer, L.; Shaw, G.; Strnad, M. Cytokinin-Derived Cyclin-Dependent Kinase Inhibitors: Synthesis and cdc2 Inhibitory Activity of Olomoucine and Related Compounds. J. Med. Chem.1997, 40, 408-412.
10 Wang, D.; De la Fuente, C.; Deng, L.; Wang, L.; Zilberman, I.; Eadie, C.;
Healey, M.; Stein, D.; Denny, T.; Harrison, L. E.; Meijer, L.; Kashanchi,
F. Inhibition of Human Immunodeficiency Virus Type 1 Transcription by Chemical Cyclin-Dependent Kinase Inhibitors. J. Virol. 2001, 75, 7266-7279.
11 McClue, S. J.; Blake, D.; Clarke, R.; Cowan, A.; Cummings, L.; Fischer, P. M.; Mackenzie, M.; Melville, J.; Stewart, K.; Wang, S.; Zhelev, N. Antiviral Activity of CYC202 in HIV-1-infected Cells. Int. J. Cancer 2002, 102, 463-468 .
12 Gray, N.; Wodicka, L.; Thunnissen, A. M.; Norman, T.; Kwon, S.; Espinoza, F. H.; Morgan, D. O.; Barnes, G.; Leclerc, S.; Meijer, L.; Kim, S. H.; Lockhart, D. J.; Schultz, P. G. Exploiting Chemical Libraries, Structure, and Genomics in the Search for New Kinase Inhibitors. Science 1998, 281, 533-538.
13 Chang, Y.; Gray, N.; Rosania, G.; Sutherlin, D.; Kwon, S.; Norman, T.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P. Synthesis and Application of Functionally Diverse 2,6,9-Trisubstituted Purine Libraries as CDK Inhibitors. Chem. Biol. 1999, 6, 361-375 .
14 Imbach, P.; Capraro, H. G.; Furet, P.; Mett, H.; Meyer, T.; Zimmermann, J. 2,6,9-Trisubstituted Purines: Optimization Towards Highly Potent and Selective CDK1 Inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 91-96 .
15 Dreyer, M. K.; Borcherding, D. R.; Dumont, J. A.; Peet, N. P.;Tsay, J. T.; Wright, P. S.; Bitonti, A. J.; Shen, J.; Kim, S. H. Crystal Structure of Human Cyclin-Dependent Kinase 2 in Complex with the Adenine-Derived Inhibitor H717. J. Med. Chem. 2001, 44, 524-530.
16 Arris, C. E.; Boyle, F. T.; Calvert, A. H.; Curtin, N. J.; Endicott, J. A.; Garman, E. F.; Gibson, A. E.; Golding, B. T.; Grant, S.; Griffin, R. J.; Jewsbury, P.; Johnson, L. N.; Lawrie, A. M.; Newell, D. R.; Noble, M. E. M.; Sausville, E. A.; Schultz, R.; Yu, M. Identification of Novel Purine and Pyrimidine Cyclin-Dependent Kinase Inhibitors with Distinct Molecular Interactions and Tumor Cell Growth Inhibition Profiles. J. Med. Chem. 2000, 43, 2797-2804 .
17 Davies, T. G.; Bentley, J.; Arris C. E.; Boyle, F. T.; Curtin, N. J.; Endicott J. A.; Gibson, A. E.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R. Structure-based Design of a Potent Purine-based Cyclin-Dependent Kinase Inhibitor. Nat. Struct. Biol. 2002, 9, 745-749.
18 Furet, P.; Zimmermann, J.; Capraro, H. G.; Meyer, T.; Imbach, P. Structure-based Design of Potent CDK1 Inhibitors Derived from Olomoucine. J. Comput. Aided Mol. Des. 2000, 14, 403-409.
19 Soni, R. Selective In Vivo and In Vitro Effects of a Small Molecule Inhibitor of Cyclin-Dependent Kinase 4. J. Natl. Cancer Inst. 2001, 93, 436-446.
20 Fischer, P. M.; Wang, S.; Clarke, R.; Jackson W.; Lyon C. E.; McClue, S.; McInnes, C.; Westwood, R.; Walkinshaw, M.; Lane, D. P. Structure-Based Design and Optimisation of Substituted 2-Phenylamino-4-(thiazol-5-yl)-Pyrimidine CDK Inhibitors. Eur. J. Cancer 2002, 38, 124.
21 Hoessel, R.; Leclerc, S.; Endicott, J. A.; Nobel, M. E.; Lawrie, A.; Tunnah, P.; Leost, M.; Damiens, E.; Marie, D.; Marko, D. Indirubin, the Active Constituent of a Chinese Antileukaemia Medicine, Inhibits Cyclin-Dependent Kinases. Nat. Cell Biol. 1999, 1, 60-67.
22 Marko, D.; Schatzle, S.; Friedel, A. Inhibition of Cyclin-Dependent Kinase 1 (CDK1) by Indirubin Derivatives In Human Tumour Cells. Br. J. Cancer 2001, 84, 283-289.
23 Davis, S. T.; Benson, B. G.; Bramson, H. N.; Chapman, D. E.; Dickerson, S. H.; Dold, K. M.; Eberwein, D. J.; Edelstein, M.; Frye, S. V.; Gampe, R. T., Jr.; Griffin, R. J.; Harris, P. A. Prevention of Chemotherapy-Induced Alopecia in Rats by CDK Inhibitors. Science 2001, 291, 134-137.
24 Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Pamela, A.; Boisclair, B. M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.; Seitz, S. P. Indenopyrazoles as Novel Cyclin Dependent Kinase (CDK) Inhibitors. J. Med. Chem. 2001, 44, 1334-1336.
25 Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Pamela A. Boisclair,B. M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.; Seitz, S. P. Synthesis and Evaluation of Indenopyrazoles as Cyclin-Dependent Kinase Inhibittors. 2. Probing the Indeno Ring Substituent Pattern. J. Med. Chem. 2002, 45, 5224-5232 .
26 Yue, E. W.; Higley, C. A.; DiMeo, S. V.; Carini, D. J.; Nugiel, D. A.; Benware, C.; Benfield, P. A.; Burton, C. R.; Cox, S.; Grafstrom, R. H.; Sharp, D. M.; Sisk, L. M.; Boylan, J. F.; Muckelbauer, J. K.; Smallwood, A. M.; Chen, H.; Chang, C. H.; Seitz, S. P.; Trainor, G. L. Synthesis and Evaluation of Indenopyrazoles as Cyclin-Dependent Kinase Inhibitors. 3. Structure Activity Relationships at C3. J. Med. Chem. 2002, 45, 5233-5248 .
27 Fry, D. W.; Bedford, D. C.; Harvey, P. H.; Fritsch, A.; Keller, P. R.; Wu, Z.; Dobrusin, E.; Leopold, W. R.; Fattaey, A.; Garrett, M. D. Cell Cycle and Biochemical Effects of PD 0183812. A Potent Inhibitor of The Cyclin D-dependent Kinases CDK4 and CDK6. J. Biol. Chem. 2001, 276, 16617-16623.
28 Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D. B.; Hunt, J. T.;
Xiao, H. Y.; Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2: Synthesis, X-ray Crystallographic Analysis, and Biological Activities. J. Med. Chem. 2002, 45, 3905-3927.
29 Takase, Y.; Saeki, T.; Watanabe, N.; Adachi, H.; Souda, S.; Saito, I. Cyclic GMP Phosphodiesterase Inhibitors. 2. Requirement of 6-Substitution of Quinazoline Derivatives for Potent and Selective Inhibitory Activity. J. Med. Chem. 1994, 37, 2106-2111.
30 Apfel, C.; Banner, D. W.; Bur, D.; Dietz, M.; Hubschwerlen, C.; Locher, H.; Marlin, F.; Masciadri, R.; Pirson, W.; Stalder, H. 2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-Dioxo-1,4- dihydro-2H-2λ6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxyacetamides as Potent and Selective Peptide Deformylase Inhibitors. J. Med. Chem. 2001, 44, 1847-1852.
31 Kurogi, Y.; Inoue, Y.; Tsutsumi, K.; Nakamura, S.; Nagao, K.; Yoshitsugu, H.; Tsuda, Y. Synthesis and Hypolipidemic Activities of Novel 2-[4-[(Diethoxyphosphoryl)methyl]phenyl]quinazolines and 4(3H)-
Quinazolinones. J. Med. Chem. 1996, 39, 1433-1437.
32 Chern, J. W.; Tao, P. L.; Yen, M. H.; Lu, G. Y.; Shiau, C. Y.; Lai, Y. J.; Chien, S. L.; Chan, C. H. Studies on Quinazolines. 5. 2,3-Dihydroimidazo[1,2-c]quinazoline Derivatives: a Novel Class of Potent and Selective. α1-Adrenoceptor Antagonists and Antihypertensive Agents. J. Med. Chem. 1993, 36, 2196-2207.
33 Chou, S. Y.; Yin, W. K.; Chung, Y. S.; Chang, L. S.; Liu, C. W.; Chen, S. F.; Shih, K. S. Kilogram-Scale Synthesis of a Highly Selective α1-Adrenoceptor Antagonist (DL-028A). Org. Pro. Res. Develop. 2002, 6, 273-278.
34 Banerjee, R.; Rachid, Z.; McNamee, J.; Claude, B. J. J. Synthesis of a Prodrug Designed to Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept. J. Med. Chem. 2003, 46, 5546-5551.
35 Shreder, K. R.; Wong, M. S.; Nomanbhoy, T.; Leventhal, P. S.; Fuller, S. R. Synthesis of AX7593, a Quinazoline-Derived Photoaffinity Probe for EGFR. Org. Lett. 2004, 6, 3715-3718.
36 Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Benfield, P. A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.,; Seitz, S. P. Indenopyrazoles as Novel Cyclin Dependent Kinase (CDK) Inhibitors. J. Med. Chem. 2001, 44, 1334-1336.
37 Honma, T.; Yoshizumi, T.; Hashimoto, N.; Hayashi, R.; Kawanishi, N.;
Fukasawa, K.; Takaki, T.; Ikeura, C. A Novel Approach for the Developmeent of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues. J. Med. Chem. 2001, 44, 4628-4640 .
38 Shewchuk, L.; Hassell, A.; Wisely, B.; Rocque, W.; Holmes, W.; Veal, J.; Kuyper, L. F. Binding Mode of the 4-Anilinoquinazoline Class of Protein Kinase Inhibitor: X-ray Crystallographic Studies of 4-Anilinoquinazolines Bound to Cyclin-Dependent Kinase 2 and p38 Kinase. J. Med. Chem. 2000, 43, 133-138.
39 Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.; Sausville, E. A.; Meijer, L.; Kunick, C. Paullones, a Series of Cyclin-Dependent Kinase Inhibitors: Synthesis, Evaluation of CDK1/Cyclin B Inhibition, and in Vitro Antitumor Activity. J. Med. Chem. 1999, 42, 2909-2919.
40 Clare, P. M.; Poorman, R. A.; Kelley, L. C.; Keith D.; Watenpaugh, K. D.; Bannow, C. A.; Karen L.; Leach, K. L. The Cyclin-Dependent Kinases CDK2 and CDK5 Act by a Random, Anticooperative Kinetic Mechanism. J. Biol. Chem. 2001, 276, 48292-48299.
41 Schneller, S. W.; Christ, W. J. Synthesis of lin-Benzofervenulin, lin -Benzotheophylline, and lin–Benzocaffeine. J. Org. Chem. 1981, 46, 1699-1702.
42 Pakrashi, S. C.; Chattpadhyaya, S.; Chakravarty, A. K. Studies on 4-Quinazolinones. Mechanism of Chromic Acid Oxidation of Arborine. J. Org. Chem. 1976, 41, 2108-2113.
43 Pakrashi, S. C.; Chattopadhy, S.; Chakravarty, A.K. Studies on 4-Quinazolinones. 8. Studies on Indian Medicinal Plants. XXXVII. Mechanism of Chromic Acid Oxidation of Arborine. J. Org. Chem. 1976, 41, 2108-2111.
44 Bodajla, M.; Stankovsky, M.; Spirkova, K. Synthesis of Some Azolylquinazolines. Coll. of Czech. Chem. Commun. 1994, 59, 1463-1466.