公开(公告)号：US06528517B1

公开(公告)日：2003-03-04

申请号：US09245019

申请日：1999-02-04

申请人： Laurence H. Hurley ,  Qingping Zeng ,  Yan Kwok ,  Jongsik Gam ,  Sean M. Kerwin

发明人： Laurence H. Hurley ,  Qingping Zeng ,  Yan Kwok ,  Jongsik Gam ,  Sean M. Kerwin

IPC分类号： A61K3144

CPC分类号： C07D498/06 ,  C07D498/16

摘要： The present invention discloses a novel quinobenzoxazine self-assembly complex on DNA and on the topoisomerase II-DNA complex. The related model is used to design a new series of quinobenzoxazines, pyridobenzophenoxazines, pyrridonaphthophenoxazines, and other related compounds that may exhibit anticancer or antibiotic activity. The anticancer activity of these compounds is thought to operate via stabilization of the topoisomerase II-DNA complex and/or interaction with G-quadruplexes, while the antibiotic activity of these compounds derives from their ability to inhibit gyrase, the bacterial type II topoisomerase.

摘要翻译： 本发明公开了一种新的喹苯偶氮自组装DNA和拓扑异构酶II-DNA复合物的复合物。 相关模型用于设计一系列可能具有抗癌活性或抗生素活性的喹喔啉恶唑，吡啶并苯并恶嗪，吡哆苯并吩ox嗪等相关化合物。 认为这些化合物的抗癌活性通过拓扑异构酶II-DNA复合物的稳定化和/或与G-四链体相互作用而起作用，而这些化合物的抗生素活性来源于它们抑制细菌II型拓扑异构酶促旋酶的能力。

公开(公告)号：US06623930B2

公开(公告)日：2003-09-23

申请号：US09940173

申请日：2001-08-27

申请人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

发明人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

IPC分类号： C12Q168

CPC分类号： C07D471/06 ,  C07D277/64 ,  C12Q1/68 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/154

摘要： Certain non-nucleoside compounds that will selectively inhibit telomerase by targeting the nucleic add structures, such as G-quadruplexes, that may be associated with human telomeres or telomerase have been identified. Inhibition of human telomerase by two perylenetetracarboxylic acid diimides and a carbocyanine has been demonstrated. 1H-NMR studies have evidenced the stabilization of a G-quadruplex by the perylenetetracarboxylic acid diimide compounds and provided evidence that these and structurally related compounds inhibit the telomerase enzyme by a mechanism consistent with interaction with G-quadruplex structures.

摘要翻译： 已经鉴定了通过靶向可能与人端粒或端粒酶相关的核酸添加结构（例如G-四链体）选择性抑制端粒酶的某些非核苷化合物。 已经证明了两种苝四羧酸二酰亚胺和羰花青对人端粒酶的抑制作用。 1 H-NMR研究证明了由苝四羧酸二酰亚胺化合物稳定G-四链体，并提供证据表明这些和结构相关的化合物通过与G-四链体结构的相互作用一致的机制来抑制端粒酶。

公开(公告)号：US6156763A

公开(公告)日：2000-12-05

申请号：US244675

申请日：1999-02-04

申请人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

发明人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

IPC分类号： C07D277/64 ,  C07D471/06 ,  C12Q1/68 ,  A61K31/44 ,  C07D221/22

CPC分类号： C07D471/06 ,  C07D277/64 ,  C12Q1/68 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/154

摘要： Certain non-nucleoside compounds that will selectively inhibit telomerase by targeting the nucleic add structures, such as G-quadruplexes, that may be associated with human telomeres or telomerase have been identified. Inhibition of human telomerase by two perylenetetracarboxylic acid diimides and a carbocyanine has been demonstrated. .sup.1 H-NMR studies have evidenced the stabilization of a G-quadruplex by the perylenetetracarboxylic acid diimide compounds and provided evidence that these and structurally related compounds inhibit the telomerase enzyme by a mechanism consistent with interaction with G-quadruplex structures.

摘要翻译： 已经鉴定了通过靶向可能与人端粒或端粒酶相关的核酸添加结构（例如G-四链体）选择性抑制端粒酶的某些非核苷化合物。 已经证明了两种苝四羧酸二酰亚胺和羰花青对人端粒酶的抑制作用。 1 H-NMR研究证明了由苝四羧酸二酰亚胺化合物稳定G-quadruplex，并提供证据表明这些和结构相关的化合物通过与G-四链体结构的相互作用一致的机制来抑制端粒酶。

公开(公告)号：US06720344B2

公开(公告)日：2004-04-13

申请号：US10108606

申请日：2002-03-27

申请人： Sean M. Kerwin ,  Laurence H. Hurley ,  Mark R. DeLuca ,  Bob M. Moore, III ,  Gregory R. Mundy

发明人： Sean M. Kerwin ,  Laurence H. Hurley ,  Mark R. DeLuca ,  Bob M. Moore, III ,  Gregory R. Mundy

IPC分类号： A61K31428

CPC分类号： C07D215/38 ,  A61K31/428 ,  A61K31/47 ,  C07D277/82

摘要： The present invention relates to methods for stimulating osteoblast proliferation and methods for selecting pharmacologically active compounds useful for stimulating osteoblast proliferation.

摘要翻译： 本发明涉及刺激成骨细胞增殖的方法和选择用于刺激成骨细胞增殖的药理学活性化合物的方法。

公开(公告)号：US06649631B1

公开(公告)日：2003-11-18

申请号：US09297188

申请日：1999-11-19

申请人： Mark W. Orme ,  Nand Baindur ,  Kirk G. Robbins ,  Scott M. Harris ,  Maria Kontoyianni ,  Laurence H. Hurley ,  Sean M. Kerwin ,  Gregory Mundy ,  Charles Petrie

发明人： Mark W. Orme ,  Nand Baindur ,  Kirk G. Robbins ,  Scott M. Harris ,  Maria Kontoyianni ,  Laurence H. Hurley ,  Sean M. Kerwin ,  Gregory Mundy ,  Charles Petrie

IPC分类号： A61K3144

CPC分类号： A61K31/44

摘要： Compounds containing two aromatic systems covalently linked through a linker containing one or more atoms, or “linker” defined as including a covalent bond per se so as to space the aromatic systems at a distance 1.5-15 Å, are effective in treating conditions associated with bone deficits. The compounds can be administered to vertebrate subjects alone or in combination with additional agents that promote bone growth or that inhibit bone resorption. They can be screened for activity prior to administration by assessing their ability to effect the transcription of a reporter gene coupled to a promoter associated with a bone morphogenetic protein and/or their ability to stimulate calvarial growth in model animal systems.

公开(公告)号：US06689887B2

公开(公告)日：2004-02-10

申请号：US09730893

申请日：2000-12-05

申请人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

发明人： Sean M. Kerwin ,  Oleg Y. Fedoroff ,  Miguel Salazar ,  Laurence H. Hurley

IPC分类号： C07D51500

CPC分类号： C07D471/06 ,  C07D277/64 ,  C12Q1/68 ,  C12Q1/6886 ,  C12Q2600/136 ,  C12Q2600/154

摘要： Certain non-nucleoside compounds that will selectively inhibit telomerase by targeting the nucleic add structures, such as G-quadruplexes, that may be associated with human telomeres or telomerase have been identified. Inhibition of human telomerase by two perylenetetracarboxylic acid diimides and a carbocyanine has been demonstrated. 1H-NMR studies have evidenced the stabilization of a G-quadruplex by the perylenetetracarboxylic acid diimide compounds and provided evidence that these and structurally related compounds inhibit the telomerase enzyme by a mechanism consistent with interaction with G-quadruplex structures.

摘要翻译： 已经鉴定了通过靶向可能与人端粒或端粒酶相关的核酸添加结构（例如G-四链体）选择性抑制端粒酶的某些非核苷化合物。 已经证明了两种苝四羧酸二酰亚胺和羰花青对人端粒酶的抑制作用。 1 H-NMR研究证明了由苝四羧酸二酰亚胺化合物稳定G-四链体，并提供证据表明这些和结构相关的化合物通过与G-四链体结构的相互作用一致的机制来抑制端粒酶。

公开(公告)号：US5922753A

公开(公告)日：1999-07-13

申请号：US808742

申请日：1997-02-28

申请人： Charles Petrie ,  Mark W. Orme ,  Nand Baindur ,  Kirk G. Robbins ,  Laurence H. Hurley ,  Sean M. Kerwin ,  Gregory R. Mundy

发明人： Charles Petrie ,  Mark W. Orme ,  Nand Baindur ,  Kirk G. Robbins ,  Laurence H. Hurley ,  Sean M. Kerwin ,  Gregory R. Mundy

IPC分类号： A61K31/4184 ,  A61K31/428 ,  A61K31/38 ,  A61K31/385

CPC分类号： A61K31/428 ,  A61K31/4184

摘要： Compounds containing two aromatic systems covalently linked through a linker containing one or more atoms, or "linker" defined as including a covalent bond per se so as to space the aromatic systems at a distance 1.5-15 .ANG., are effective in treating conditions associated with bone deficits. The compounds can be administered to vertebrate subjects alone or in combination with additional agents that promote bone growth or that inhibit bone resorption. They can be screened for activity prior to administration by assessing their ability to effect the transcription of a reporter gene coupled to a promoter associated with a bone morphogenetic protein and/or their ability to stimulate calvarial growth in model animal systems.

摘要翻译： 包含通过含有一个或多个原子的接头共价连接的两个芳族体系的化合物或定义为包含共价键本身的“连接体”，以使芳族体系在距离为1.5-15安培的范围内空间有效地处理与 骨缺损。 化合物可以单独施用于脊椎动物，或者与促进骨生长或抑制骨吸收的其它试剂组合施用。 可以通过评估其在影响与骨形态发生蛋白相关的启动子相关的报告基因的转录和/或刺激模型动物系统中颅骨生长的能力的能力来筛选其给药前的活性。

公开(公告)号：US06593306B1

公开(公告)日：2003-07-15

申请号：US09467932

申请日：1999-12-21

申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

IPC分类号： A61K3170

CPC分类号： A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/708 ,  C07H19/14

摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2′-deoxyquanosine-5′-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

公开(公告)号：US6054442A

公开(公告)日：2000-04-25

申请号：US675119

申请日：1996-07-03

申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miguel Salazar ,  Blain Mamiya ,  Bradford E. Windle ,  Makoto Wajima

发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miguel Salazar ,  Blain Mamiya ,  Bradford E. Windle ,  Makoto Wajima

IPC分类号： A61K31/70 ,  C07H19/14

CPC分类号： A61K31/7076 ,  A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/708 ,  C07H19/14

摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

公开(公告)号：US07294643B2

公开(公告)日：2007-11-13

申请号：US10720991

申请日：2003-11-24

申请人： Sean M. Kerwin

发明人： Sean M. Kerwin

IPC分类号： A61K31/423 ,  A61K31/195 ,  C07C233/66 ,  C07D263/56 ,  C07D263/57

CPC分类号： C07D263/57 ,  C07D235/18 ,  C07D413/04

摘要： The present invention includes a number of structural analogues of UK-1. A comparision of the anticancer activity of the UK-1 analogues with their ability to inhibit the growth of methicillin-sensitive and methicillin-resistant Staphylococcus aureus demonstrates that a structurally simplified analogue of UK-1 retains the natural product's selective activity against cancer cells. Structurally conservative changes to UK-1 that diminish Mg2+-binding ability may result in a dramatic decrease in cancer cell cytotoxicity. The results may establish a minimum structural pharmacophore as well as a functional role for Mg2+-binding in the selective cytotoxicity of UK-1.

摘要翻译： 本发明包括许多UK-1的结构类似物。 UK-1类似物的抗癌活性与其抑制甲氧西林敏感和耐甲氧西林金黄色葡萄球菌生长的能力的比较表明，UK-1的结构简化类似物保留天然产物对癌细胞的选择性活性。 降低Mg 2+结合能力的UK-1的结构保守变化可导致癌细胞细胞毒性的显着降低。 结果可以建立最小结构药效团以及在UK-1的选择性细胞毒性中的Mg 2+结合的功能性作用。