Terrapin Technologies, Inc.

Telik, Inc.

Matthew H Lyttle

Lawrence M Kauvar

Richard F Borch

Apparao Satyam

Amy S Morgan

Steven R Schow

Robert T Lum

Hugo O Villar

Michael R Kozlowski

Thomas Redelmeier

Robert W Macsata

Michael D Hocker

Pharmaceutical compositions and methods of using them. Lipid formulations of a glutathione analog and methods of manufacturing them. Their use to stimulate hematopoiesis, protect hematopoietic cells from damage caused by radiation or chemotherapy, or potentiate the stimulatory action of one or a combination of cytokines on colony formation by hematopoietic progenitor cells, protect a subject from a destructive effect of a chemotherapeutic agent or irradiation, or to potentiate the effect of a chemotherapeutic agent.

Therapeutic compositions containing glutathione analogs

Compounds of the formula ##STR1## or the alkyl (1-6C), alkenyl (1-6C), or arylalkyl (7-12C) amides or salts including the cycloamido forms thereof; wherein

Glutathione analogs as reagents

Compounds of the formula ##STR1## and the esters, amides, amide/esters and salts thereof, wherein YCO is .gamma.-glu or .beta.-asp;

Metabolic effects of certain glutathione analogs

Compounds of the formula ##STR1## or of the formula ##STR2## or the amides, esters or salts thereof, wherein: S.sup.x is S.dbd.O, O.dbd.S.dbd.O, S.dbd.NH, HN.dbd.S.dbd.O, Se.dbd.O, O.dbd.Se.dbd.O, Se.dbd.NH, HN.dbd.Se.dbd.O, S.sup.+ R.sup.3 wherein R.sup.3 is alkyl (1-6C) or O--C.dbd.O or HN--C.dbd.O;

Urethane mediated, GST specific molecular release systems

Compounds wherein a biologically active molecule is coupled to a glutathione analog through a conjugated system which permits activation of the biologically active molecule while retaining the biologically active molecule tethered to the glutathione analog are useful as tethered prodrugs that slow the rate of clearance of an active biomolecule through the multidrug resistance pump.

Tethered prodrugs

Solid phase supported synthesis of peptides and other molecules using protecting groups comprising p-nitrobenzyl is described.

P-nitrobenzyl side-chain protection for solid-phase synthesis

A method to potentiate the effect of a chemotherapeutic agent in a tumor cell, which method comprises administering to said tumor cell, along with said chemotherapeutic agent, a potentiating amount of a compound of the formula: ##STR1## or an amide, ester or hybrid amide/ester thereof, wherein X is a hydrocarbon radical optionally substituted on any aromatic moiety contained therein; Y--CO is .gamma.-Glu or .beta.-Asp and AA.sub.C is an amino acid, preferably glycine, phenylglycine, .beta.-alanine, alanine or phenylalanine is disclosed. Similar compounds can also be used to selectively exert cytotoxicity versus target cells as compared to nontarget cells and also to elevate the production of GM progenitors in bone marrow of mammalian subjects.

Target-selective protocols based on mimics

Bone marrow stimulation by certain glutathione analogs

Compounds of the formula ##STR1## or the alkyl (1-6C), alkenyl (1-6C), or arylalkyl (7-12C) amides or salts including the cycloamido forms thereof;

Glutathione analogs and paralog panels comprising glutathione mimics

A process for preparing a trinucleotide phosphoramidite comprising reacting a 3',5'-dihydroxy dinucleoside with a nucleoside 5'-phosphoramidite; oxidizing this trinucleotide phosphite to produce the 3'-hydroxyl trinucleotide; and finally converting the 3'-hydroxy trinucleotide to the 3'-phosphoramidite derivative. Such trinucleotide phosphoramidites provide a convenient route for synthesizing oligonucleotides with randomized codons at specified positions.

Process for preparing codon amidites

Compounds of the formula: ##STR1## or a salt thereof, wherein n is 1 or 2; wherein when n is 1, X is a mono- or disubstituted or unsubstituted C.sub.1-20 hydrocarbon radical wherein any substitution is selected from the group consisting of halo, OR, and SR, wherein R is H or C.sub.1-4 alkyl; and wherein, when n is 2, one X is defined as for n=1 and the other X is lower C.sub.1-4 alkyl; ##STR2## wherein m is 1 or 2; AA.sub.C is an amino acid coupled through a peptide bond to the remainder of the compound of Formula (1) selected from the group consisting of glycine, valine, alanine, 4-aminobutyric acid, aspartic acid, phenylglycine, histidine, tryptophan, tyrosine, and phenylalanine, wherein the phenyl group of phenylalanine or phenylglycine may optionally contain a single substitution selected from the group consisting of halo, OR, and SR, wherein R is H or C.sub.1-4 alkyl; with the proviso that if Y is ##STR3## AA.sub.C is not Gly; and if Y is ##STR4## and X is benzyl, AA.sub.C cannot be Val are useful as affinity ligands and as diagnostic reagents. These compounds and analogous tripeptide glutathione analogs can be used as members of panels to obtain specific characteristic profiles for various glutathione-S-transferases.

Compounds of the formula ##STR1## or the alkyl (1-6 C), alkenyl (1-6 C), or arylalkyl (7-12 C) amides or salts including the cycloamido forms thereof;

Compounds of the formula: ##STR1## or the amides, esters or salts thereof, wherein: L is an electron withdrawing leaving group;

Glutathione S-transferase-activated compounds

Compounds of the formula: ##STR1## or the amides, esters or salts thereof, wherein: L is an electron withdrawing leaving group; S.sup.x is S=O, O=S=O, S=NH, HN=S=O, Se=O, O=Se=O, Se=NH, HN=Se=O, S+R.sup.4 wherein R.sup.4 is alkyl (1-6 C), or O--C=O or HN--C=O; each R of R.sup.1, R.sup.2 and R.sup.3 is independently H or a noninterfering substituent; n is 0, 1 or 2; Y is selected from the group consisting of ##STR2## wherein m is 1 or 2; and AA.sub.C is an amino acid linked through a peptide bond to the remainder of said compound of formula 1, are dislosed. These compounds are useful prodrugs for selective treatment of target tissues which contain compatible glutathione S-transferase (GST) isoenzymes.

Growing community of inventors

Point Reyes Station, CA, United States of America

Matthew H Lyttle