US 6,143,492 AGranted

Optical molecular sensors for cytochrome P450 activity

AssigneeAurora Biosciences Corporation

InventorsLewis R. Makings, Gregor Zlokarnik

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Abstract

The invention provides a compound, useful as an optical probe or sensor of the activity of at least one cytochrome P450 enzyme, and methods of using the compound to screen candidate drugs, and candidate drugs identified by these methods. The optical probe of the invention is a compound having the generic structure Y-L-Q, wherein Y is selected from the group consisting of Q as herein defined, saturated C.sub.1 -C.sub.20 alkyl, unsaturated C.sub.1 -C.sub.20 alkenyl, unsaturated C.sub.1 -C.sub.20 alkynyl, substituted saturated C.sub.1 -C.sub.20 alkyl, substituted unsaturated C.sub.1 -C.sub.20 alkenyl, substituted unsaturated C.sub.1 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 cycloalkyl, C.sub.1 -C.sub.20 cycloalkenyl, substituted saturated C.sub.1 -C.sub.20 cycloalkyl, substituted unsaturated C.sub.1 -C.sub.20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (--O(substituted ortho-phenyl)CR.sup.2 H).sub.p --, (--O(substituted meta-phenyl)CR.sup.2 H).sub.p --, and (--O(substituted para-phenyl)CR.sup.2 H).sub.p --, wherein for each p, all R.sup.2 are separately selected from the group consisting of a hydrogen atom, saturated C.sub.1 -C.sub.20 alkyl, unsaturated C.sub.1 -C.sub.20 alkenyl, unsaturated C.sub.1 -C.sub.20 alkynyl, substituted saturated C.sub.1 -C.sub.20 alkyl, substituted unsaturated C.sub.1 -C.sub.20 alkenyl, substituted unsaturated C.sub.1 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 cycloalkyl, C.sub.1 -C.sub.20 cycloalkenyl, substituted saturated C.sub.1 -C.sub.20 cycloalkyl, substituted unsaturated C.sub.1 -C.sub.20 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve; and Q is a chemical moiety that gives rise to optical properties in its hydroxy or hyrdoxylate, phenol or phenoxide form that are different from the optical properties that arise from its ether form. Most preferably, p is one, R.sup.2 is hydrogen, and Q is the ether form of a phenoxide fluorophore.

A compound having the structure:

Y-L-Q, wherein:
Y is selected from the group consisting of Q as herein defined, saturated C.sub.1 -C.sub.20 alkyl, unsaturated C.sub.1 -C.sub.20 alkenyl, unsaturated C.sub.1 -C.sub.20 alkynyl, substituted saturated C.sub.1 -C.sub.20 alkyl, substituted unsaturated C.sub.1 -C.sub.20 alkenyl, substituted unsaturated C.sub.1 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 cycloalkyl, C.sub.1 -C.sub.20 cycloalkenyl, substituted saturated C.sub.1 -C.sub.20 cycloalkyl, substituted unsaturated C.sub.1 -C.sub.20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
wherein if Y is selected from Q as herein defined, L is L', wherein L' is selected from the group of --(CR.sup.4 H)(--O(substituted ortho-phenyl)CR.sup.2 H).sub.p --, --(CR.sup.4 H)(--O(substituted meta-phenyl)CR.sup.2 H).sub.p --, and --(CR4H)(--O(substituted para-phenyl)CR.sup.2 H).sub.p --, wherein each R.sup.2 and each R.sup.4 is separately selected from the group consisting of a hydrogen atom, saturated C.sub.1 -C.sub.20 alkyl, unsaturated C.sub.1 -C.sub.20 alkenyl, unsaturated C.sub.1 -C.sub.20 alkynyl, substituted saturated C.sub.1 -C.sub.20 alkyl, substituted unsaturated C.sub.1 -C.sub.20 alkenyl, substituted unsaturated C.sub.1 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 cycloalkyl, C.sub.1 -C.sub.20 cycloalkenyl, substituted saturated C.sub.1 -C.sub.20 cycloalkyl, substituted unsaturated C.sub.1 -C.sub.20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl and p is a positive integer no greater than twelve;
L has the chemical structure L' or (--O(substituted ortho-phenyl)CR.sup.2 H).sub.p --, (--O(substituted meta-phenyl)CR.sup.2 H).sub.p --, and (--O(substituted para-phenyl)CR.sup.2 H).sub.p --, wherein each R.sup.2 is separately selected from the group consisting of a hydrogen atom, saturated C.sub.1 -C.sub.20 alkyl, unsaturated C.sub.1 -C.sub.20 alkenyl, unsaturated C.sub.1 -C.sub.20 alkynyl, substituted saturated C.sub.1 -C.sub.20 alkyl, substituted unsaturated C.sub.1 -C.sub.20 alkenyl, substituted unsaturated C.sub.1 -C.sub.20 alkynyl, C.sub.1 -C.sub.20 cycloalkyl, C.sub.1 -C.sub.20 cycloalkenyl, substituted saturated C.sub.1 -C.sub.20 cycloalkyl, substituted unsaturated C.sub.1 -C.sub.20 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and p is a positive integer no greater than twelve;
and
Q is a chemical means for generating an altered optical signal via cleavage of a C--O bond.

3 more elements

Abstract

Claims79