Silicon based drug conjugates and methods of using same

Abstract

Described herein are silicon based conjugates capable of delivering one or more payload moieties to a target cell or tissue. Contemplated conjugates may include a silicon-heteroatom core, one or more optional catalytic moieties, a targeting moiety that permits accumulation of the conjugate within a target cell or tissue, one or more payload moieties (e.g., a therapeutic agent or imaging agent), and two or more non-interfering moieties covalently bound to the silicon-heteroatom core.

1 .- 52 . (canceled) 
     
     
         53 . A silicon based conjugate having the formula 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein: 
         L is a targeting moiety that permits selective accumulation of the conjugate within a target cell or tissue; 
         R P  is P; 
         P is a payload moiety; 
         Y 1  is represented by the formula:
   -LL 1 -G 1 -LL 2 -; 
 
         Y 2  is a bond 
         G 1  is an optional catalytic moieties each independently selected from the group consisting of -heteroaryl-, —O-heteroaryl-, —NR a -heteroaryl-, —S(O) w -heteroaryl- (wherein w is 0, 1, or 2), —NR a —SO 2 -heteroaryl-, —SO 2 —NR a -heteroaryl-, -phenyl-, —O-phenyl-, —NR a -phenyl-, —S(O) w -phenyl- (wherein w is 0, 1, or 2), —NR a —SO 2 -phenyl-, —SO 2 —NR a -phenyl-, —C(O)—C 0-6 alkyl-, —C(O)—O—C 0-6 alkyl-, —O—C(O)—C 0-6 alkyl-, —NR a —C(O)—C 0-6 alkyl-, —C(O)—NR a —C 0-6 alkyl-, and —NR a —C 0-6 alkyl-; wherein -heteroaryl-, —O-heteroaryl-, —NR a -heteroaryl-, —S(O) w -heteroaryl- (wherein w is 0, 1, or 2), —NR a —SO 2 -heteroaryl-, —SO 2 —NR a -heteroaryl-, -phenyl-, —O-phenyl-, —NR a -phenyl-, —S(O) w -phenyl- (wherein w is 0, 1, or 2), —NR a —SO 2 -phenyl-, —SO 2 —NR a -phenyl-, may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, —COOH, —C(O)—O—C 1-6 alkyl, —C(O)—NR a R b , —NR a —C(O)—C 1-6 alkyl, —C(O)—NR a —SO 2 —C 1-6 alkyl, —SO 3 H, —SO 2 —NR a R b , —NR a —SO 2 —C 1-6 alkyl, and —SO 2 —NR a —C 1-6 alkyl; 
         LL 1  and LL 2 , are spacer moieties each independently selected from the group consisting of a bond and C 1-20 alkylene, wherein one, two, three or four methylene units of C 1-20 alkylene are optionally and independently replaced by C 3-8 cycloalkylene, C 2-10 alkenylene C 2-10 alkynylene, aryl, heteroaryl, amino acids, polypeptides, —NR 1Y —, —N(R 1Y )C(O)—, —C(O)N(R 1Y )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 1Y )—, —NR 1Y —C 1-15 alkyl-NR 1Y —C(O)—; —(CH 2 —CH 2 —O) s —, —(O—CH 2 —CH 2 ) s —, —NR 1Y —(CH 2 —CH 2 —O) s —C 1-6 alkyl-NR 1Y —C(O)—; —(O—CH 2 —CH 2 ) s —NR 1Y —C(O)—; —S—C 0-6 alkyl-; —NR 1Y —C 1-6 alkyl-; —N(C 1-3 alkyl)-C 1-6 alkyl-NH—C(O)—; —NH—C 1-6 alkyl-N(C 1-3 alkyl)-C(O)—; —SO 2 —NR 1Y —C 0-6 alkyl-; —N(R 1Y )SO 2 —C 0-6 alkyl-; —SO 2 -heterocyclyl-C 0-6 alkyl-; -heterocyclyl-C(O)—; -heterocyclyl-C 0-6 alkyl-NR 1Y —C(O)—; —NR 1Y —C 0-6 alkylene-heterocyclyl-C(O)—; —O—C 1-6 alkylene-C(O)—; —O—C 1-15 alkylene-NR 1Y —C(O)—; —O—C 1-15 alkylene-C(O)—NR 1Y —; and —O—C 1-6 alkylene-; 
         wherein, independently for each occurrence, R 1Y  is selected from the group consisting of H, C 1-6 alkyl, cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic; and 
         s is an integer from 1-15; 
         R 1  and R 2  are each independently selected from the group consisting of methyl, 
         isopropyl, and tert-butyl; and 
         R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, and phenyl may be optionally substituted; 
         or R a  and R b , together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, or N; wherein the 4-7 membered heterocyclic ring is optionally substituted. 
       
     
     
         54 . The silicon based conjugate of  claim 53 , wherein the conjugate is substantially stable in aqueous solution having a pH of at least 7 and hydrolytically cleaves in aqueous solution having a pH less than 7 to release the payload moiety from the conjugate. 
     
     
         55 . The silicon based conjugate of  claim 53 , wherein the targeting moiety selectively binds or recognizes at least one of: cell surface receptors, transporters, and antigens that are overexpressed in a disease state. 
     
     
         56 . The silicon based conjugate of  claim 53 , wherein the targeting moiety is capable of binding to at least one of: a cell surface receptor, a cognate ligand of a cell surface receptor, an antigen, and a cell wall. 
     
     
         57 . The silicon based conjugate of  claim 53 , wherein the payload moiety is selected from the group consisting of antigens, proteins, cytotoxic agents, metabolic modulators, anti-inflammatory agents, anti-viral agents, pathway modulators, synthetic lethal combinations, siRNA, mRNA, miRNA, endosomal escape enhancers, and imaging agents. 
     
     
         58 . The silicon based conjugate of  claim 53 , wherein the payload moiety is an antimitotic agent, an actin binding agent, a vinca alkaloid, a platinum-containing compound, a HDAC inhibitor, a thymidylate synthase inhibitor, a nitrogen mustard, 5-fluorouracil (5-FU), or its derivatives. 
     
     
         59 . The silicon based conjugate of  claim 53 , wherein the payload moiety is taxane, colchicine, colcemid, nocadozole, vinblastine, cytochalasin, latrunculin, halloidin, vincristine cytochalasin, latrunculin, halloidin, lenalidomide, pomalidomide, camptothecin, topotecan, combretastatins, capecitabine, gemcitabine, suberoylanilidehydroxamic acid (SAHA)), metformin, methotrexate, pemetrexed, raltitrexed, bendamustine, or melphalan. 
     
     
         60 . A silicon based conjugate having the formula 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein: 
         L is a targeting moiety that permits selective accumulation of the conjugate within a target cell or tissue; 
         R P  is P; 
         P is a payload moiety; 
         Y 1  is represented by the formula:
   -LL 1 -G 1 -LL 2 -; 
 
         Y 2  is is a bond 
         G 1  is an optional catalytic moieties each independently selected from the group consisting of -heteroaryl-, —O-heteroaryl-, —NR a -heteroaryl-, —S(O) w -heteroaryl- (wherein w is 0, 1, or 2), —NR a —SO 2 -heteroaryl-, —SO 2 —NR a -heteroaryl-, -phenyl-, —O-phenyl-, —NR a -phenyl-, —S(O) w -phenyl- (wherein w is 0, 1, or 2), —NR a —SO 2 -phenyl-, —SO 2 —NR a -phenyl-, —C(O)—C 0-6 alkyl-, —C(O)—O—C 0-6 alkyl-, —O—C(O)—C 0-6 alkyl-, —NR a —C(O)—C 0-6 alkyl-, —C(O)—NR a —C 0-6 alkyl-, and —NR a —C 0-6 alkyl-; wherein -heteroaryl-, —O-heteroaryl-, —NR a -heteroaryl-, —S(O) w -heteroaryl- (wherein w is 0, 1, or 2), —NR a —SO 2 -heteroaryl-, —SO 2 —NR a -heteroaryl-, -phenyl-, —O-phenyl-, —NR a -phenyl-, —S(O) w -phenyl- (wherein w is 0, 1, or 2), —NR a —SO 2 -phenyl-, —SO 2 —NR a -phenyl-, may optionally be substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, —COOH, —C(O)—O—C 1-6 alkyl, —C(O)—NR a R b , —NR a —C(O)—C 1-6 alkyl, —C(O)—NR a —SO 2 —C 1-6 alkyl, —SO 3 H, —SO 2 —NR a R b , —NR a —SO 2 —C 1-6 alkyl, and —SO 2 —NR a —C 1-6 alkyl; 
         LL 1  and LL 2  are spacer moieties each independently selected from the group consisting of a bond and C 1-20 alkylene, wherein one, two, three or four methylene units of C 1-20 alkylene are optionally and independently replaced by C 3-8 cycloalkylene, C 2-10 alkenylene C 2-10 alkynylene, aryl, heteroaryl, amino acids, polypeptides, —NR 1Y —, —N(R 1Y )C(O)—, —C(O)N(R 1Y )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 1Y )—, —NR 1Y —C 1-15 alkyl-NR 1Y —C(O)—; —(CH 2 —CH 2 —O) s —, —(O—CH 2 —CH 2 ) s —, —NR 1Y —(CH 2 —CH 2 —O) s —C 1-6 alkyl-NR 1Y —C(O)—; —(O—CH 2 —CH 2 ) s —NR 1Y —C(O)—; —S—C 0-6 alkyl-; —NR 1Y —C 1-6 alkyl-; —N(C 1-3 alkyl)-C 1-6 alkyl-NH—C(O)—; —NH—C 1-6 alkyl-N(C 1-3 alkyl)-C(O)—; —SO 2 —NR 1Y —C 0-6 alkyl-; —N(R 1Y )SO 2 —C 0-6 alkyl-; —SO 2 -heterocyclyl-C 0-6 alkyl-; -heterocyclyl-C(O)—; -heterocyclyl-C 0-6 alkyl-NR 1Y —C(O)—; —NR 1Y —C 0-6 alkylene-heterocyclyl-C(O)—; —O—C 1-6 alkylene-C(O)—; —O—C 1-15 alkylene-NR 1Y —C(O)—; —O—C 1-15 alkylene-C(O)—NR 1Y —; and —O—C 1-6 alkylene-; 
         wherein, independently for each occurrence, R 1Y  is selected from the group consisting of H, C 1-6 alkyl, cycloalkyl, haloalkyl, halocycloalkyl, heteroalkyl, heterocycloalkyl, heterohaloalkyl, heterohalocycloalkyl, aryl, biaryl, heteroaryl, heterobiaryl, mono or bicyclic heterocyclic; and 
         s is an integer from 1-15; 
         R 1  and R 2  are each independently selected from the group consisting of methyl, 
         isopropyl, and tert-butyl; and 
         R a  and R b  are independently selected, for each occurrence, from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and phenyl; wherein C 1-6 alkyl, C 2-6 alkenyl, and phenyl may be optionally substituted; 
         or R a  and R b , together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from O, S, or N; 
         wherein the 4-7 membered heterocyclic ring is optionally substituted. 
       
     
     
         61 . The silicon based conjugate of  claim 60 , wherein the conjugate is substantially stable in aqueous solution having a pH of between 7 and 7.5 and hydrolytically cleaves in aqueous solution having a pH less than 7 or greater than 7.5 to release the payload moiety from the conjugate. 
     
     
         62 . The silicon based conjugate of  claim 60 , wherein the targeting moiety selectively binds or recognizes at least one of: cell surface receptors, transporters, and antigens that are overexpressed in a disease state. 
     
     
         63 . The silicon based conjugate of  claim 60 , wherein the targeting moiety is capable of binding to at least one of: a cell surface receptor, a cognate ligand of a cell surface receptor, an antigen, and a cell wall. 
     
     
         64 . The silicon based conjugate of  claim 60 , wherein the payload moiety is selected from the group consisting of antigens, proteins, cytotoxic agents, metabolic modulators, anti-inflammatory agents, anti-viral agents, pathway modulators, synthetic lethal combinations, siRNA, mRNA, miRNA, endosomal escape enhancers, and imaging agents. 
     
     
         65 . The silicon based conjugate of  claim 60 , wherein the payload moiety is an antimitotic agent, an actin binding agent, a vinca alkaloid, a platinum-containing compound, a HDAC inhibitor, a thymidylate synthase inhibitor, a nitrogen mustard, 5-fluorouracil (5-FU), or its derivatives. 
     
     
         66 . The silicon based conjugate of  claim 60 , wherein the payload moiety is taxane, colchicine, colcemid, nocadozole, vinblastine, cytochalasin, latrunculin, halloidin, vincristine cytochalasin, latrunculin, halloidin, lenalidomide, pomalidomide, camptothecin, topotecan, combretastatins, capecitabine, gemcitabine, suberoylanilidehydroxamic acid (SAHA)), metformin, methotrexate, pemetrexed, raltitrexed, bendamustine, or melphalan.