High-throughput method to rapidly add chemical moieties to a small molecule library
Organic compounds for target identification, drug discovery, chemical library production, high-throughput screening, fluorophore conjugation, chemiluminescent compound conjugation, creation of proximity induced modulators (e.g., protein degraders)/chimeric molecules, or a combination thereof are described. The compounds can contain small molecule moieties for identification of their potential targets; an isocyanate, photoactivatable groups; chemical moieties for enrichment and detection of target-small molecule moiety interactions; proximity induced modulator element; fluorophores; chemiluminescent groups; or combinations thereof.
1 . A compound having a structure:
wherein:
when present R 1 is-OH or NR 2 R 3 , —NR 2 C(O)R 3 , R 2 and R 3 are independently hydrogen, unsubstituted alkyl, or substituted alkyl,
Z is a small molecule moiety having a molecular weight less than 2,500 Da,
X is O, NR′, or S,
QQ is absent, one or more resins, or well plates,
wherein, when QQ is absent, W 1 comprises a carboxyl group, optionally-C(O) OH; a carbonyl group, optionally —C(O)R 1w ); an ester, optionally —C(O)OR 1w or —OC(O)R 1w ; an amide optionally —C(O)NR 2w R 3w or —NR 2w C(O)R 3w ; a thioester, optionally —C(O)SR 4w or —SC(O)R 4w ; a hydrazide, optionally —C(O)NHNH 2 ; an amine; or a carbinol, optionally —CH 2 OH,
wherein, when QQ is present, W 1 comprises —OC(O)—, —C(O)O—, —NR 2w C(O)—, —NR 2w —, —C(O)—, —C(O)S—, —SC(O)—, —NHNHC(O)—, —S—, —O—, or a combination thereof
wherein R′, R 1w -R 4w are independently hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocyclyl, substituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, substituted hydroxyamino, or unsubstituted hydroxyamino.
2 . The compound of claim 1 , wherein W1 comprises —C(O)OH, —C(O)R 1w , —C(O)OR 1w , —OC(O)R 1w , —C(O)NR 2w R 3w , —NR 2w C(O)R 3w , —C(O)SR 4w , —SC(O)R 4w , —C(O)NHNH 2 , or —CH 2 OH, wherein R 2w and R 3w independently hydrogen, unsubstituted alkyl, or substituted alkyl.
3 . The compound of claim 1 , wherein the one or more resins are selected from the group consisting of trityl resins, hydrazinobenzyol resins, Dawson Dbz AM resins, sulfonamide resins, HMBA resins, Merrifield resins, PAM resins, BHA resins, MBHA resins, Wang resins, brominated Wang resins, 4-nitrobenzophenone oxime resins, 4-(hydroxymethyl) phenoxyacetic acid resins, HMPB resins, Rink acid resins, Rink amide resins, PAL resins, Sieber amide resins, 4-sulfoamoylbenzoyl resins, aminoalkylated resins, hydroxyalkylated resins, brominated polystyrene resins, bromoalkylated resins, acrylamide-PEG copolymer resins, 4-(4-formyl-3-methoxyphenoxy) ethyl resins, melamine resins, acrylate resins, epoxy resins, urethane resins, silicone resins, fluoropolymer resins, and a combination thereof.
4 . A collection of compounds comprising a plurality of the compounds of claim 1 .
5 . A method for the synthesis of the collection of compounds of claim 4 , the method comprising:
(i) reacting one or more compounds with the surface of a resin or well plate to attach the one or more compounds to the resin or to the well plate via W1.
6 . The method of claim 5 , wherein the one or more compounds of step (i) comprise a carboxyl, a carbonyl, an amine, a hydroxyl, a thiol, a hydrazine, a hydroxylamine, an ester, a thioester, or a combination thereof.
7 . The method of claim 5 further comprising:
(ii) reacting one or more additional compounds with at least one of the one or more compounds in step (i) attached on the surface of the resin or well plate to form —NHC(O)X—.
8 . The method of claim 7 , wherein reacting the one or more additional compounds of step (ii) to form —NHC(O)X— involves an isocyanate functional group.
9 . The compound of claim 1 , wherein Z has a molecular weight between 70 Da and 2,500 Da.