US2002045764A1PendingUtilityA1
Tubulin binding compounds (COBRA)
Est. expiryJun 29, 2018(expired)· nominal 20-yr term from priority
C07D 493/10C07K 14/47C07C 323/41C07D 307/42C07D 307/12
47
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Claims
Abstract
Novel tubulin binding compounds having potent tubulin depolymerization activity and inhibitory activity against tubulin polymerization. The compounds are effective agents for inhibiting cellular proliferation, for example, in cancer cells. The compounds are adapted to interact favorably with a novel tubulin binding pocket, which pocket is useful for screening of anti-tubulin, anti-proliferation, and anti-cancer drugs.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of the formula
wherein
X is O, S, C, or NR a R b ;
R is a saturated or unsaturated (C 7 -C 15 ) hydrocarbon chain;
R 1 and R 2 are independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, C 1 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, aryl, or heteroaryl;
Y 1 and Y 2 are independently H, OH, SH, CN, halogen, acyl, (C 1 -C 6 )alkoxy, thioacyl, (C 1 -C 6 )alkylthio, or NR a R b , provided that Y 1 and Y 2 are not both hydrogen;
n is 1 to 3;
m is 0 to 10; and
each S is independently OH, SH, CO 2 H, halogen, CN, acyl, thioacyl, ester, thioester, alkoxy, aryloxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, (C 3 -C 7 )cycloalkyl, aryl, heteroaryl, C(═O)NR a R b , or NR a R b ; taken together, two of S can form a ring or any two adjacent carbons can form a double bond;
where R a and R b are each independently hydrogen, acyl, alkyl, (C 3 -C 7 )cycloalkyl, aryl, or heteroaryl; or R a and R b together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino.
2 . The compound of claim 1 , having the formula:
3 . The compound of claim 1 , having the formula:
4 . The compound of claim 1 , having the formula:
5 . A compound of claim 1 , having the formula:
6 . A compound of the formula:
wherein R is a saturated or unsaturated (C 7 -C 15 ) hydrocarbon chain;
Y is H, OH, SH, CN, halogen, acyl, (C 1 -C 6 )alkoxy, thioacyl, (C 1 -C 6 )alkylthio, or NR a R b ; where R a and R b are each independently wherein R a and R b are each independently hydrogen, acyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, or heteroaryl; or R a and R b together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino;
D is a (C 5 -C 12 ) hydrocarbon comprising at least one heteroatom, and having at least one hydrogen binding group; and
X comprises C, S, N, P, or O.
7 . A compound of claim 6 , wherein said hydrogen binding group comprises OH, SH, CN, halogen, acyl, (C 1 -C 6 )alkoxy, thioacyl, (C 1 -C 6 )alkylthio, or NR a R b .
8 . The compound of claim 7 , wherein D comprises two or more carbonyl groups.
9 . The compound of claim 1 , wherein X is O.
10 . The compound of claim 1 , wherein R is a saturated (C 7 -C 1 5 )hydrocarbon.
11 . The compound of claim 1 , wherein R 1 is hydrogen and R 2 is H, CH 2 OH, or CH 2 CH 2 CH═CH 2 .
12 . The compound of claim 1 , wherein Y 1 and Y 2 are each OH.
13 . The compound of claim 1 , wherein n is 1.
14 . The compound of claim 13 , wherein two adjacent S form a double bond.
15 . A compound of claim 1 , wherein one or more of R, R 1 , R 2 , Y 1 , Y 2 , D, R a , and R b are independently substituted with OH, SH, CO 2 H, halogen, CN, acyl, thioacyl, ester, thioester, (C 1 -C 6 )alkoxy, (C 1 -C 6 )aryloxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )arylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl,(C 3 -C 7 )cycloalkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )heteroaryl, C(═O)NR a R b or NR a R b ; wherein R a and R b are each independently hydrogen, acyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )heteroaryl, or R a and R b together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino; taken together, any two S 1 and S 2 can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached.
16 . A compound of claim 6 , wherein R is a saturated (C 7 -C 15 )hydrocarbon.
17 . A compound of claim 6 , wherein one or more of R, R 1 , R 2 , Y 1 , Y 2 , D, R a , and R b are independently substituted with OH, SH, CO 2 H, halogen, CN, acyl, thioacyl, ester, thioester, (C 1 -C 6 )alkoxy, (C 1 -C 6 )aryloxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )arylthio, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )heteroaryl, C(═O)NR a R b or NR a R b ; wherein R a and R b are each independently hydrogen, acyl, (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 6 -C 10 )aryl, or (C 6 -C 10 )heteroaryl, or R a and R b together with the nitrogen to which they are attached form a ring such as pyrrolidino, piperidino, morpholino, or thiomorpholino; taken together, any two S 1 and S 2 can form a ring, and any two adjacent substituents can form a double bond between the two carbons to which they are attached.
18 . The compound of claim 6 , wherein X comprises S.
19 . The compound of claim 6 , wherein D comprises a chloromethylketone group.
20 . A composition comprising the compound of claim 1 and a carrier.
21 . A composition comprising the compound of claim 6 and a carrier.
22 . A method for inhibiting the polymerization or inducing depolymerization of tubulin comprising administering to tubulin a compound of claim 1 .
23 . A method for inhibiting proliferation of cells comprising contacting said cells with a compound of claim 1 .
24 . A method for inhibiting the proliferation of tumor cells, comprising administering to said tumor cells an inhibitory amount of the compound of claim 1 - 6 .
25 . A method for treating cancer in a patient, comprising administering to said patient an effective inhibitory dose of a compound of claim 1 - 6 .
26 . A binding pocket of tubulin, comprising
an elongated, narrow channel capable of accomodating a linear aliphatic chain of approximately 12 carbon atoms, positioned between the GDP/GTP binding site and the taxol binding site of tubulin; approximate dimensions of 6 Å×22 Å×7 Å; and a plurality of leucine and/or isoleucine residues (providing a highly binding environment in the binding pocket.
27 . A method for treating a cellular proliferation disorder, comprising administering to a patient a compound of claim 1 to inhibit cell proliferation.
28 . A compound of the formula:
where R is an aliphatic chain having approximately 12 carbon residues, and is adapted to favorably interact with the elongate, narrow channel of the COBRA binding pocket of tubulin;
where D is a (C 3 -C 15 )hydrocarbon comprising at least one heteroatom and one or more hydrogen bonding group, where D is adapted to favorably interact with one or more of Asp367 or Asn226 of the COBRA binding pocket of tubulin; and
wherein the molecule is adapted to fit the dimensions of the COBRA binding pocket.
29 . The compound of claim 28 , wherein R is adapted to interact favorably with one or more of the following tubulin amino acid residues:
Leu217, Val275, Ile276, Leu368, Ile212, Ile234, Leu230, His229, Ile209, Ile231, and Leu23.
30 . The compound of claim 28 , wherein the compound has a molecular volume of less than about 600 Å 3 .
31 . A synthetic compound configured and arranged to favorably interact with the COBRA binding pocket of claim 27 .
32 . The compound of claim 31 , configured and arranged to interact favorably with one or more of the following tubulin amino acid residues: Asp367 or Asn26.
33 . The compound of claim 31 , configured and arranged to interact favorably with one or more of the following tubulin amino acid residues: Leu217, Val275, Ile276, Leu368, Ile212, Ile234, Leu230, His229, Ile209, Ile231, and Leu23.
34 . A synthetic tubulin binding compound having a structure which binds the COBRA binding pocket of claim 27 .
35 . The compound of claim 34 , comprising one or more functional group that forms hydrogen bonds, covalent bonds, or ionic bonds with one or more of Asp367 or Asn226 of the COBRA binding pocket.
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