CA2407967A1 - Tubulin binding ligands and corresponding prodrug constructs - Google Patents

Tubulin binding ligands and corresponding prodrug constructs Download PDF

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CA2407967A1
CA2407967A1 CA002407967A CA2407967A CA2407967A1 CA 2407967 A1 CA2407967 A1 CA 2407967A1 CA 002407967 A CA002407967 A CA 002407967A CA 2407967 A CA2407967 A CA 2407967A CA 2407967 A1 CA2407967 A1 CA 2407967A1
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compound
alkyl
contain
benzyl
nhp
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CA2407967C (en
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Kevin G. Pinney
Vani P. Mocharla
Zhi Chen
Charles M. Garner
Anjan Ghatak
Mallinath Hadimani
Jimmy Kessler
James M. Dorsey
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Baylor University
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Baylor University
Kevin G. Pinney
Vani P. Mocharla
Zhi Chen
Charles M. Garner
Anjan Ghatak
Mallinath Hadimani
Jimmy Kessler
James M. Dorsey
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract

A diverse set of tubulin binding ligands have been discovered which are structural by characterized, in a general sense, by a semi-rigid molecular framework capable of maintaining aryl-aryl, pseudo pi stacking distances appropriate for molecular recognition of tubulin. In phenolic or amino form, these ligands may be further functionalized to prepare phosphate esters, phosphate salts, and phosphoramides capable of demonstrating selective targeting and destruction of tumor cell vasculature.

Claims (43)

1. A compound of the structure:

2. A compound of the structure:

3. A compound of the structure:

4. A compound of the structure:

5. A compound of the structure:

wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR1, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, while the remaining of R1 through R5 are hydrogen atoms.
6. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O-M+)2) or phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms.
7. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O-M+)2) or phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms, and R7 is H, or an alkyl or branched alkyl.
8. A compound of the structure:
9. A compound of the structure:
10. A compound of the structure:
11. A compound of the structure:
12. A compound of the structure:
wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR1, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, while the remaining of R1 through R5 are hydrogen atoms.
13. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O-M+)2) or phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms.
14. A compound of the structure:

wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O-M+)2) or phosphoramidate (-NHP(O)(O-M+)2) moiety where M = an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms, and R7 is H, or an alkyl or branched alkyl.
15. A compound of the structure:

wherein R1 through R6 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR7R8) where R7 and R8 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents or R1 through R6 contain one phenolic moiety and one amino moiety while of the remaining R1 through R6 one is substituted with an alkoxy group and the rest hydrogen atoms.
16. A compound of the structure:

wherein R1 through R6 contain at least two phosphate esters (-OP(O)(O- M+)2) or two phosphoramidates (-NHP(O)(O-M+)2) moieties where M is an alkali metal canon;
or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl, or aryl substituent (the two R groups are the same or different), or R1 through R6 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R6 one is substituted with an alkoxy group and the rest hydrogen atoms.
17. A compound of the structure:

wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, while the remaining of R1 through R5 are hydrogen atoms.
18. A compound of the structure:

wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms.
19. A compound of the structure:

wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms, and R7 is H, or an alkyl or branched alkyl.
20. A compound of the structure:

wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, while the remaining of R1 through R5 are hydrogen atoms.
21. A compound of the structure:

wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms.
22. A compound of the structure:

wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms, and R7 is H, or an alkyl or branched alkyl.
23. A compound of the structure:

wherein R1 through R6 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR7R8 ) where R7 and R8 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, or R1 through R6 contain one phenolic moiety and one amino moiety while of the remaining R1 through R6 one is a methoxy group (-OCH3) and the rest hydrogen atoms.
24. A compound of the structure:

wherein R1 through R6 contain at least two phosphate esters (-OP(O)(O- M+)2) or two phosphoramidate moieties (-NHP(O)(O- M+)2) where M is an alkali metal cation;
or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or R1 through R6 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R6 one is a methoxy group (-OCH3) and the rest hydrogen atoms.
25. A compound of the structure:

26. A compound of the structure:

27. A compound of the structure:

28. A compound of the structure:

29. A compound of the structure:

30. A compound of the structure:

31. A compound of the structure:

32. A compound of the structure:

wherein Y is either NH, S, or O, and R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or a metal cation.
33. A compound of the structure:

wherein Y is either NH, S, or O, and R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or a metal cation.
34. A compound of the structure:

wherein R1 through R4 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, or R1 through R4 contain one phenolic moiety and one amino moiety, while of the remaining R1 through R4 one is a methoxy group (-OCH3) and one is a hydrogen atom.
35. A compound of the structure:

wherein R1 through R4 contain at least two phosphate esters (-OP(O)(O-M1)2) or two phosphoramidate moieties (-NHP(O)(O- M+)2) where M is an alkali metal cation;
or (-NHP(O)(OR)2) where R is chosen to be any appropriate alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or R1 through R4 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R4 one is a methoxy group (-OCH3) and one is a hydrogen atom.
36. A compound of the structure:

wherein If R1 is -OH or -NH2 then R2 is H, and if R2 is -OH or -NH2 then R1 is H.
37. A compound of the structure:

wherein Y is either NH, S, or O, and R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups may be the same or different), or a metal cation.
38. A compound of the structure:

wherein Y is either NH, S, or O, and R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or a metal cation.
39. A compound of the structure:

wherein R1 through R4 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, where R1 through R4 contain one phenolic moiety and one amino moiety, while of the remaining R1 through R4 one is a methoxy group (-OCH3) and one is a hydrogen atom.
40. A compound of the structure:

wherein R1 through R4 contain at least two phosphate ester (-OP(O)(O- M+)2) or two phosphoramidate moieties (-NHP(O)(O- M+)2) where M is an alkali metal cation;
or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), where R1 through R4 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R4 one is a methoxy group (-OCH3) and one is a hydrogen atom.
41. A compound of the structure:

wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, while the remaining of R1 through R5 are hydrogen atoms.
42. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are hydrogen atoms.
43. A compound of the structure:
wherein R1 through R6 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR7R8) where R7 and R8 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, where R1 through R6 contain one phenolic moiety and one amino moiety, while of the remaining R1 through R6 one is substituted with a methoxy group (-OCH3) and the rest hydrogen atoms.

4. A compound of the structure:
wherein R1 through R6 contain at least two phosphate ester (-OP(O)(O- M+)2) or two phosphoramidates (-NHP(O)(O- M+)2) moieties where M is an alkali metal cation;
or (-NHP(O)(OR)2) or where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or R1 through R6 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R6 one is substituted with a methoxy group (-OCH3) and the rest hydrogen atoms.

45. A compound of the structure:
46. A compound of the structure:
wherein R1 is a phenolic moiety (-OH) or an amino group (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl or aryl substituents, while R2 is H, alkyl, branched alkyl, aryl, (alkoxy aryl, or phenolic aryl moieties), benzyl, alkoxy benzyl, phenolic benzyl or vinyl.

47. A compound of the structure:
wherein R1 contains a phosphate ester (-OP(O)(O-M+)2) or a phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while R2 is H, alkyl, branched alkyl, aryl, (alkoxy aryl or phenolic aryl moieties), benzyl, alkoxy benzyl, phenolic benzyl or vinyl.

48. A compound of the structure:
wherein R1 contains a phenolic moiety (-OH) or an amino group (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl or branched alkyl substituents, while R2 is H, alkyl, branched alkyl, aryl (may contain alkoxy and phenolic moieties), benzyl (may contain alkoxy and phenolic moieties on the aryl ring), or vinyl.

49. A compound of the structure:
wherein R1 contains a phosphate ester (-OP(O)(O-M+)2) or a phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl, or aryl substituent (the two R groups are the same or different), while R2 is H, alkyl, branched alkyl, aryl, (alkoxy aryl or phenolic aryl moieties), benzyl, alkoxy benzyl, phenolic benzyl or vinyl.

50. A compound of the structure:
wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl or branched alkyl substituents, while the remaining R1 through R5 contain at least one alkoxy group (branched or straight chain) with the remaining R groups are hydrogen atoms, and n is 1, 2, or 3.

51. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M = an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl, or aryl substituent (the two R groups are the same or different), while at least one of the remaining R1 through R5 are at least one branched or straight chain alkoxy group and the remaining R
groups substituted with hydrogen atoms, and n is 1, 2, or 3.

52. A compound of the structure:
wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2, NHR, or NR6R7 where R6 and R7 are the same or different alkyl, branched alkyl, benzyl or aryl substituents, while the remaining R1 through R5 contain at least one branched or straight chain alkoxy group with the remaining R groups substituted with a hydrogen atom, and n is 1, 2, or 3.

53. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O- M+)2) or a phosphoramidate (-NHP(O)(O- M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1 through R5 are at least one branched or straight chain alkoxy group and the remaining R groups substituted with a hydrogen atom, and n is 1, 2, or 3.

54. A compound of the structure:
wherein R1 through R5 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR6R7) where R6 and R7 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, or R1 through R5 contain one phenolic moiety and one amino moiety, while of the remaining R1 through R5 one is a methoxy group (-OCH3) and the rest hydrogen atoms, and n is 1, 2, or 3.

55. A compound of the structure:
wherein R1 through R5 contain at least two phosphate esters (-OP(O)(O- M+)2) or two phosphoramidates (-NHP(O)(O-M+)2) moieties where M is an alkali metal ration;
or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), or R1 through R5 contain one phosphate ester and one phosphoramidate, while of the remaining R1 through R5 one is substituted with a methoxy group (-OCH3) and the rest hydrogen atoms, and n is 1, 2, or 3.

56. A compound of the structure:
wherein R1 through R5 contain at least one phenolic moiety (-OH) or at least one amino group (NH2,NHR or NR6R7) where R6 and R7 are the same or different an alkyl, branched alkyl, benzyl, or aryl substituents,, while the remaining of R1 through R5 are hydrogen atoms.

57. A compound of the structure:
wherein R1 through R5 contain at least one phosphate ester (-OP(O)(O-M+)2) or phosphoramidate (-NHP(O)(O-M+)2) moiety where M is an alkali metal cation; or (-NHP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R groups are the same or different), while the remaining of R1through R5 are hydrogen atoms.

58. A compound of the structure:
wherein R1 through R6 contain at least two phenolic moieties (-OH) or at least two amino groups (NH2, NHR, or NR7R8) Where R7 and R8 are the same or different alkyl, branched alkyl, benzyl, or aryl substituents, or R1 through R6 contain one phenolic moiety and one amino moiety, while of the remaining R1through R6 one is substituted with a methoxy group (-OCH3) and the rest hydrogen atoms.

59. A compound of the structure:
wherein R1 through R6 contain at least two phosphate ester (-OP(O)(O- M+)2) or two phosphoramidate (-NP(O)(O- M+)2) moieties where M is an alkali metal cation;
or (-NP(O)(OR)2) where R is an alkyl, branched alkyl, benzyl or aryl substituent (the two R
groups are the same or different), or R1 through R6 contain one phosphate ester and one phosphoramidate, while of the remaining R1through R6 one is a methoxy group (-OCH3) and the rest hydrogen atoms.

60. A method for inhibiting tubulin polymerization by contacting a tubulin-containing system with an effective amount of a compound described in any claims 1-59.

61. The method of claim 60 wherein said system is a tumor cell.

62. A method of treating a host afflicted with a neoplastic disease by administering to said host a compound described in any of claims 1-59.

63. The method of claims 60, 61, and 62 wherein the contacted system is located in a patient.

64. The method of claim 60 for treating cancer, wherein said cancer may be chosen from the group containing leukemia, lung, colon, thyroid, CNS, melanoma, ovarian, renal, prostate, and breast cancers.

65. A preparation for pharmaceutical use containing a compound from any of claims 1-59 as the active component along with a pharmaceutically acceptable carrier.

66. A method for selectively targeting and destroying tumor vasculature with an effective amount of a compound described in any of claims 1-59.

67. A method for treating macular degeneration and related diseases of the eye caused or enhanced by vascularization comprising administering an effective amount of a compound described in any of claims 1-59.

68. A method for treating psoriasis by administering an effective amount of a compound described in any of claims 1-59.

69. A method for treating arthritis by administering an effective amount of a compound described in any of claims 1-59.

70. A method for treating a disease or condition caused or enhanced by vascularization, the method comprising administering an effective amount of a compound in any of claims 1-59.

71. A method for treating ocular (corneal and retinal) neovascularization by administering an effective amount of a compound described in any of claims 1-59.

72. A method for conversion of a 3-oxygenated-4-methoxyacetophenone to the corresponding .alpha.-halo-4-methoxyacetophenone by treatment of the corresponding trimethylsilyl enol ether with elemental halogen.

73. The method of claim 72 wherein the halo is bromo and the halogen is bromine.

74. The method of claim 72 wherein the halo is chloro or iodo and the halogen is chlorine or iodine.

75. A method for conversion of a 3-oxygenated-4-methoxyacetophenone to the corresponding .alpha.-bromo-4-methoxyacetophenone by treatment of the corresponding trimethylsilyl enol ether with elemental bromine.

76. A method for conversion of a mono-oxygenated-mono-alkoxylated-acetophenone to the corresponding .alpha.-bromo-mono-oxygenated-mono-alkoxylated-acetophenone by treatment of the corresponding trimethylsilyl enol ether with elemental bromine.

77. A method for conversion of a di-oxygenated-mono-alkoxylated-acetophenone to the corresponding .alpha.-bromo-di-oxygenated-mono-alkoxylated-acetophenone by treatment of the corresponding trimethylsilyl enol ether with elemental bromine.

78. A method for conversion of an acetophenone to the corresponding .alpha.-bromo-acetophenone by treatment of the corresponding trimethylsilyl enol ether with elemental bromine.
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Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7001926B2 (en) 2000-03-10 2006-02-21 Oxigene, Inc. Tubulin binding agents and corresponding prodrug constructs
US7091240B2 (en) 2000-03-10 2006-08-15 Oxigene, Inc. Tubulin binding ligands and corresponding prodrug constructs
AUPR283801A0 (en) * 2001-02-01 2001-03-01 Australian National University, The Chemical compounds and methods
US7632955B2 (en) 2001-12-13 2009-12-15 National Health Research Institutes Indole compounds
TWI317634B (en) 2001-12-13 2009-12-01 Nat Health Research Institutes Aroyl indoles compounds
US7528165B2 (en) 2001-12-13 2009-05-05 National Health Research Institutes Indole compounds
US20050245489A1 (en) * 2004-05-03 2005-11-03 Pinney Kevin G Chromene-containing compounds with anti-tubulin and vascular targeting activity
US7456214B2 (en) 2004-05-03 2008-11-25 Baylor University Chromene-containing compounds with anti-tubulin and vascular targeting activity
AU2005273961A1 (en) * 2004-08-11 2006-02-23 Williamsburg Holdings Llc Noncardiotoxic pharmaceutical compounds
WO2006057946A2 (en) * 2004-11-22 2006-06-01 Threshold Pharmaceuticals, Inc. Tubulin binding anti cancer agents and prodrugs thereof
US20060148674A1 (en) * 2004-12-31 2006-07-06 Luduena Richard F Therapeutic composition
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
EP1919882A2 (en) * 2005-02-17 2008-05-14 Synta Pharmaceuticals Corporation Isoxazole combretastatin derivatives for the treatment of proliferative disorders
US7265248B1 (en) 2005-04-29 2007-09-04 Technology Innovations, Llc Compositions and methods for the treatment of malaria
JP5354775B2 (en) * 2005-06-14 2013-11-27 ベイラー ユニバーシティ Combretastatin analogs with tubulin binding activity
EP1984333B1 (en) 2006-02-03 2012-04-25 Bionomics Limited Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerisation inhibitors
EP2203049A2 (en) * 2007-09-17 2010-07-07 The Trustees of Columbia University in the City of New York Synthesis of resveratrol-based natural products
ES2529434T3 (en) * 2007-11-21 2015-02-20 Oxigene, Inc. Method to treat hematopoietic neoplasms
CN102596929A (en) 2009-08-27 2012-07-18 生物学特性有限公司 Treatment of macular degeneration
NZ598489A (en) 2009-08-27 2014-03-28 Bionomics Ltd Combination therapy for treating proliferative diseases
US9353150B2 (en) 2012-12-04 2016-05-31 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment
EP2972394A4 (en) 2013-03-15 2016-11-02 Sloan Kettering Inst Cancer Hsp90-targeted cardiac imaging and therapy
US11419934B2 (en) 2015-08-18 2022-08-23 Oncotelic Therapeutics, Inc. Use of VDAS to enhance immunomodulating therapies against tumors
WO2017066668A1 (en) * 2015-10-15 2017-04-20 Baylor University Drug-linker conjugate pharmaceutical compositions
US10512631B2 (en) * 2015-10-23 2019-12-24 Beth Israel Deaconess Medical Center, Inc. Chalcone compounds
WO2017197045A1 (en) 2016-05-11 2017-11-16 Movassaghi Mohammad Convergent and enantioselective total synthesis of communesin analogs
WO2018209239A1 (en) 2017-05-11 2018-11-15 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
WO2020247054A1 (en) 2019-06-05 2020-12-10 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2401322A1 (en) 1977-08-22 1979-03-23 Thore Bernard IMPROVEMENTS TO ENGINE SYSTEMS INCLUDING A SUPERCHARGED INTERNAL COMBUSTION ENGINE
US4996237A (en) * 1987-01-06 1991-02-26 Arizona Board Of Regents Combretastatin A-4
CA1338645C (en) * 1987-01-06 1996-10-15 George R. Pettit Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"
JP2963288B2 (en) 1992-01-14 1999-10-18 株式会社海洋バイオテクノロジー研究所 Water-based harmful organism control agent
TW325458B (en) 1993-09-08 1998-01-21 Ajinomoto Kk Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer
US5731353A (en) 1993-09-08 1998-03-24 Ajinomoto Co., Inc. Stilbene derivatives and pharmaceutical compositions containing them
US5596106A (en) 1994-07-15 1997-01-21 Eli Lilly And Company Cannabinoid receptor antagonists
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
IL117276A (en) * 1995-02-28 2001-10-31 Lilly Co Eli Benzothiophene compounds, their preparation and pharmaceutical compositions comprising them
US5856340A (en) 1995-02-28 1999-01-05 Eli Lilly And Company Method of treating estrogen dependent cancers
TW334418B (en) 1995-03-07 1998-06-21 Ajinomoto Kk Stilbene derivatives and pharmaceutical compositions
US5596786A (en) * 1995-06-09 1997-01-28 Kluiters; Gam Triangular shaped floor mop
CA2214070C (en) 1996-08-29 2006-03-14 Eli Lilly And Company Dihydronaphthalene and naphthalene compounds, intermediates, formulations, and methods
US5886025A (en) 1997-03-06 1999-03-23 Baylor University Anti-mitotic agents which inhibit tubulin polymerization
NZ501822A (en) 1997-10-02 2001-12-21 Yukijirushi Nyugyo Kabushiki K Therapeutic agents for male and female sex hormone dependent diseases
GB9725953D0 (en) 1997-12-08 1998-02-04 Pfizer Ltd Compounds useful in therapy
US6162930A (en) * 1998-03-06 2000-12-19 Baylor University Anti-mitotic agents which inhibit tubulin polymerization
FR2777886B1 (en) * 1998-04-27 2002-05-31 Adir NOVEL BENZOTHIOPHENIC, BENZOFURANIC AND INDOLIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US6110963A (en) 1998-05-12 2000-08-29 American Home Products Corporation Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6166069A (en) 1998-05-12 2000-12-26 American Home Products Corporation Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
US6060488A (en) 1998-09-22 2000-05-09 Eli Lilly And Company Benzothiophenes for treating estrogen deficiency
JP2002537262A (en) * 1999-02-18 2002-11-05 オキシジェン，インコーポレイティド Compositions and methods for use in targeting vascular disruption
WO2001092224A1 (en) 2000-05-31 2001-12-06 Astrazeneca Ab Indole derivatives with vascular damaging activity

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