Optical molecular sensors for cytochrome P450 activity
First Claim
1. A compound having the structure:
- Y-L-Q, wherein;
Y is selected from the group consisting of Q as herein defined, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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 --(CR4 H)(--O(substituted ortho-phenyl)CR2 H)p --, --(CR4 H)(--O(substituted meta-phenyl)CR2 H)p --, and --(CR4H)(--O(substituted para-phenyl)CR2 H)p --, wherein each R2 and each R4 is separately selected from the group consisting of a hydrogen atom, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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)CR2 H)p --, (--O(substituted meta-phenyl)CR2 H)p --, and (--O(substituted para-phenyl)CR2 H)p --, wherein each R2 is separately selected from the group consisting of a hydrogen atom, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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.
8 Assignments
0 Petitions
Accused Products
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 C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 cycloalkenyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; L is selected from the group of (--O(substituted ortho-phenyl)CR2 H)p --, (--O(substituted meta-phenyl)CR2 H)p --, and (--O(substituted para-phenyl)CR2 H)p --, wherein for each p, all R2 are separately selected from the group consisting of a hydrogen atom, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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, R2 is hydrogen, and Q is the ether form of a phenoxide fluorophore.
-
Citations
79 Claims
-
1. A compound having the structure:
-
Y-L-Q, wherein; Y is selected from the group consisting of Q as herein defined, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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 --(CR4 H)(--O(substituted ortho-phenyl)CR2 H)p --, --(CR4 H)(--O(substituted meta-phenyl)CR2 H)p --, and --(CR4H)(--O(substituted para-phenyl)CR2 H)p --, wherein each R2 and each R4 is separately selected from the group consisting of a hydrogen atom, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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)CR2 H)p --, (--O(substituted meta-phenyl)CR2 H)p --, and (--O(substituted para-phenyl)CR2 H)p --, wherein each R2 is separately selected from the group consisting of a hydrogen atom, saturated C1 -C20 alkyl, unsaturated C1 -C20 alkenyl, unsaturated C1 -C20 alkynyl, substituted saturated C1 -C20 alkyl, substituted unsaturated C1 -C20 alkenyl, substituted unsaturated C1 -C20 alkynyl, C1 -C20 cycloalkyl, C1 -C20 cycloalkenyl, substituted saturated C1 -C20 cycloalkyl, substituted unsaturated C1 -C20 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79)
-
-
23. A compound selected from the group consisting para methoxybenzyl resorufin (MOBR) and methoxybenzyloxy-4-trifluorocoumarin (MOBFC).
-
33. A method of quantifying the activity of a CYP450 enzyme by using at least one of MOBR and MOBFC compounds.
Specification
-
- Resources
-
Current AssigneeLife Technologies Corporation (Thermo Fisher Scientific Incorporated)
-
Original AssigneeAurora Biosciences Corporation (Vertex Pharmaceuticals Incorporated)
-
InventorsZlokarnik, Gregor, Makings, Lewis R.
-
Primary Examiner(s)Leary, Louise N.
-
Application NumberUS09/301,395Time in Patent Office559 DaysField of Search435/4, 435/25, 435/968US Class Current435/4CPC Class CodesC07D 265/38 [b, e]-condensed with two s...C07D 311/16 substituted in position 7C07D 311/82 XanthenesC07D 493/10 Spiro-condensed systemsC12Q 1/26 involving oxidoreductaseY10S 435/968 High energy substrates, e.g...
