Compounds for the detection of senescent cells
AssigneeThe University of Manchester
InventorsVassilis Gorgoulis, Paul Townsend, Panayiotis Marakos, Nikolaos Lougiakis, Nicole Pouli, Nikolaos Kastrinakis
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Abstract
The present disclosure relates to de novo synthesized, chemical compounds of the formula (1) or (2) that function as senescent cell detectors wherein R1, R2, R3, R4 and Z are as defined herein. The present invention also relates to processes for the preparation of these compounds, to their use in the detection of senescent cells, to methods of detecting senescence in cells and to kits comprising said compounds. The compounds have the ability to react with lipofuscin, in an analogous manner to the histochemical dye Sudan Black B (SBB).
Claims24
A compound that functions as a senescent cell detector of the general formula (2), shown below:
- wherein:
- R1 and R2 are each independently selected from:
- i) hydrogen, with the proviso that only one of R1 and R2 can be hydrogen in general structure (2) above,
- ii) an optionally substituted (1-10C)alkyl group;
- iii) an optionally substituted aryl group;
- iv) an optionally substituted (1-10C)alkyl-aryl group;
- v) an optionally substituted aryl-(1-10C)alkyl group;
- or
- vi) R1 and R2 are linked so as to form part of a spiranic cycloalkane group, selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or adamantanyl;
- R3 is hydrogen or (1-10C)alkyl group;
- R4 is hydrogen, or one or more of the following substituents:
- i) a halogen selected from F, Cl, Br and I;
- ii) NO2;
- iii) CF3;
- iv) SCH3;
- v) an optionally substituted (1-5C)alkyl group;
- vi) a (1-10C)alkoxy group which optionally comprises one or more heteroatoms;
- and
- Z is either Z1 or —Ar—Z1;
- and Z1 is selected from OH, NH2, O(CH2)nCH2OH, (CH2)qOH or COOH, wherein n is an integer selected from 1 to 9, and wherein q is an integer selected from 1 to 4, and wherein Ar is an aryl group optionally substituted with one or more of the following substituents halogen, (1-6C)alkyl, (1-6C)alkenyl or (1-5C)alkoxy;
- and
- wherein, unless otherwise specified, optionally substituted refers to the optional substitution by one or more substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, aryl, heteroaryl, (1-6C)alkyl, (3-8C)cycloalkyl and (1-6C)alkoxy.
A compound being selected from any one of the following:
A method for detecting senescence, comprising contacting a compound of the general formula (1) or (2) with a sample of single or mixed cells, optionally in the presence of lipofuscin:
- wherein:
- R1 and R2 are each independently selected from:
- i) hydrogen, with the proviso that R2 is not hydrogen in general structure (1) above and only one of R1 and R2 can be hydrogen in general structure (2) above,
- ii) an optionally substituted (1-10C)alkyl group;
- iii) an optionally substituted aryl group;
- iv) an optionally substituted (1-10C)alkyl-aryl group;
- v) an optionally substituted aryl—(1-10C)alkyl group:
- or
- vi) R1 and R2, are linked so as to form part of a spiranic cycloalkane group, selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or adamantanyl;
- R3 is hydrogen or (1-10C) alkyl group;
- R4 is hydrogen, or one or more of the following substituents:
- i) a halogen selected from F, Cl, Br and I:
- ii) NO2;
- iii) CF3;
- iv) SCH3;
- v) an optionally substituted (1-5C)alkyl group:
- vi) a(1-10C)alkoxy group which optionally comprises one or more heteroatoms;
- and
- Z is either Z1 or —Ar—Z1—and Z1 is selected from OH, NH2, O(CH2)0CH2OH, (CH2)0OH or COOH, wherein n is an integer selected from 1 to 9, and wherein q is an integer selected from 1 to 4 and wherein Ar is an aryl group optionally substituted with one or more of the following substituents halogen, (1-6C)alkyl, (1-6C)alkenyl or (1-5C)alkoxy;
- and
- wherein, unless otherwise specified, optionally substituted refers to the optional substitution by one or more substituents selected from the group consisting of halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, aryl, heteroaryl, (1-6C)alkyl, (3-8C)cycloalkyl and (1-6C)alkoxy.
Dependencies are inferred from the claim text.