Lipid-like nanocomplexes and uses thereof

Abstract

Disclosed are compounds of formula (I) below: wherein each of the variables A, B, X, W, V, R 1 -R 5 , and m is defined herein. Also disclosed are pharmaceutical compositions containing a nanocomplex, wherein the nanocomplex is formed of one of the compounds, and a protein, a nucleic acid, or a small molecule; and methods of treating a medical condition with one of the pharmaceutical compositions.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof; 
         wherein 
       
       
         
           
           
               
               
           
         
         A, a hydrophilic head, is an amino moiety formed from 
         B is C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 24  cycloalkyl, C 1 -C 24  heteroalkyl, C 1 -C 24  heterocycloalkyl, aryl, or heteroaryl, or 
       
       
         
           
           
               
               
           
         
         each occurrence of R 1  and R 2  is independently a C 1 -C 20  bivalent aliphatic radical; 
         each occurrence of R 3  and R 4 , independently, is H or C 1 -C 10  alkyl, or R 3  and R 4 , together with the atom to which they are attached, form C 3 -C 10  cycloalkyl; 
         each occurrence of R 5  is independently C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 24  cycloalkyl, Cl-C 24  heteroalkyl, Cl-C 24  heterocycloalkyl, aryl, or heteroaryl; 
         each occurrence of W is independently O, S, or Se; 
         each occurrence of V is independently a bond, O, S, or Se; 
         each occurrence of X, a linker, is independently 
       
       
         
           
           
               
               
           
         
         in which each occurrence of L 1 , L2, L 3 , and L 4 , independently, is a bond, O, S, or 
         NR c ; each occurrence of G is independently O, S, or NR d ; each occurrence of Q is independently OR f , SR g , or NR h R 1 ; and each occurrence of r and t, independently, is 1-6, each occurrence of R c , R d , R f , R g , R h , and R i , independently, is H, C 1 -C 10  alkyl, C 1 -C 10  heteroalkyl, aryl, or heteroaryl; and 
         m is independently at each occurrence 0 or 1, provided that m is 1 when V is S. 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein each X is 
       
         
           
           
               
               
           
         
       
       and each of R c  and R d , independently, is H or C 1 -C 10  alkyl. 
     
     
         5 . The compound of  claim 1 , wherein each of R 1  and R 2  is a C 1 -C 4  bivalent aliphatic radical; each of R 3  and R 4 , independently, is H or C 1 -C 4  alkyl; and R 5  is C 1 -C 20  alkyl. 
     
     
         6 . The compound of  claim 1 , wherein W is O, S, or Se; and V is a bond. 
     
     
         7 . The compound of  claim 1 , wherein each of W and V, independently, is O or Se, and m is 0. 
     
     
         8 . The compound of  claim 1 , wherein each of W and V is O or S; and m is 1. 
     
     
         9 .- 16 . (canceled) 
     
     
         17 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof; 
         wherein 
         A, a hydrophilic head, is an amino moiety formed from 
       
       
         
           
           
               
               
           
         
         B is C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 24  cycloalkyl, C 1 -C 24  heteroalkyl, C 1 -C 24  heterocycloalkyl, aryl, or heteroaryl, or 
       
       
         
           
           
               
               
           
         
         each occurrence of R 1  is independently a C 1 -C 20  bivalent aliphatic radical; 
         each occurrence of R 2  is independently a bond or C 1 -C 20  bivalent aliphatic radical; 
         each occurrence of R 3  and R 4 , independently, is H or C 1 -C 10  alkyl, or R 3  and R 4 , together with the atom to which they are attached, form C 3 -C 10  cycloalkyl; 
         each occurrence of R 5  is independently 
       
       
         
           
           
               
               
           
         
         in which each occurrence of R 6  is independently a bond or C 1 -C 20  bivalent aliphatic 
         radical; each occurrence of R b  and R b ′ is independently F or, R b  and R b ′, together 
         with the atom to which they are attached, form C═O; each occurrence of R 7  is F or an 
         aliphatic lipid moiety; each occurrence of L 1  and L 2 , independently, is a bond, O, S, 
         or NR c , each occurrence of R c  is independently H, C 1 -C 10  alkyl, C 1 -C 10  heteroalkyl, 
         aryl, or heteroaryl; and n is independently at each occurrence an integer from 1 to 20; each occurrence of W and V, independently, is a bond, O, S, or Se; 
         each occurrence of X, a linker, is independently 
       
       
         
           
           
               
               
           
         
       
       in which each occurrence of L 3 , L 4 , L 5 , and L 6 , independently, is a bond, O, S, or NR c ; each occurrence of G is independently O, S, or NR d ; each occurrence of Q is independently OR f , SR g , or NR h R 1 ; and each occurrence of r and t, independently, is 1-6, each occurrence of R c , R d , R e , R f , R g , R h , and R i , independently, is H, C 1 -C 10  alkyl, C 1 -C 10  heteroalkyl, aryl, or heteroaryl; and
 m is independently at each occurrence 0 or 1. 
 
     
     
         18 . The compound of  claim 17 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 17 , wherein each of R 1  and R 2  is a C 1 -C 4  bivalent aliphatic radical; and each of R 3  and R 4 , independently, is H or C 1 -C 4  alkyl. 
     
     
         20 . The compound of  claim 17 , wherein each of L 1  and L 2  is a bond, and each of R b , R b ′, and R 7  is F. 
     
     
         21 . The compound of  claim 17 , wherein each of R 2 , W, and V is a bond, and m is 0. 
     
     
         22 . The compound of  claim 19 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 22 , wherein R 1  is a C 1 -C 4  bivalent aliphatic radical; and X is 
       
         
           
           
               
               
           
         
         each occurrence of R c  and R d , independently, is H or C 1 -C 10  alkyl. 
       
     
     
         24 - 25 . (canceled) 
     
     
         26 . The compound of  claim 17 , wherein R 6  is C 1 -C 4  bivalent aliphatic radical; each occurrence of L 1  and L 2 , independently, is O or NR c , each occurrence of R c  is independently H or C 1 -C 10  alkyl; R b  and R b ′, together with the atom to which they are attached, form C═O; n is independently at each occurrence 1 or 2; and R 7  is an aliphatic lipid moiety. 
     
     
         27 . The compound of  claim 26 , wherein R 7  is an aliphatic lipid moiety formed from cholesterol. 
     
     
         28 . The compound of  claim 26 , wherein each of R 1  and R 2  is a C 1 -C 4  bivalent aliphatic radical; X is 
       
         
           
           
               
               
           
         
         each of R c  and R d , independently, are H or C 1 -C 10  alkyl; each of W and V, independently, is 0, S, or Se; and m is 0. 
       
     
     
         29 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising a nanocomplex, wherein the nanocomplex is formed of a compound of  claim 1 , and a protein or a nucleic acid; wherein the nanocomplex has a particle size of 50 nm to 1000 nm, and the compound binds to the protein or nucleic acid via a non-covalent interaction, a covalent bond, or both. 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein the protein is GFP-Cre or CRISPR/Cas9. 
     
     
         33 . A pharmaceutical composition comprising a nanocomplex, wherein the nanocomplex is formed of a compound of  claim 17 , and a protein or a nucleic acid; wherein the nanocomplex has a particle size of 50 nm to 1000 nm, and the compound binds to the protein or nucleic acid via a non-covalent interaction, a covalent bond, or both. 
     
     
         34 . The pharmaceutical composition of  claim 33 , wherein the protein is GFP-Cre or CRISPR/Cas9. 
     
     
         35 . A method of treating a medical condition, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of  claim 31 . 
     
     
         36 . A method of treating a medical condition, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of  claim 33 . 
     
     
         37 . A pharmaceutical composition comprising a nanocomplex, wherein the nanocomplex is formed of a compound of  claim 1 , and a small molecule; wherein the nanocomplex has a particle size of 50 nm to 1000 nm, and the compound binds to the small molecules via a non-covalent interaction, a covalent bond, or both. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the small molecule is an antifungal agent or a chemotherapeutic agent. 
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the small molecule is selected from the group consisting of Bortezomib, Imatinib, Gefitinib, Erlotinib, Afatinib, Osimertinib, Dacomitinib, Daunorubicin hydrochloride, cytarabine, Fluorouracil, Irinotecan Hydrochloride, Vincristine Sulfate, Methotrexate, Paclitaxel, Vincristine Sulfate, epirubicin, docetaxel, Cyclophosphamide, Carboplatin, Lenalidomide, Ibrutinib, Abiraterone acetate, Enzalutamide, Pemetrexed, Palbociclib, Nilotinib, Everolimus, Ruxolitinib, epirubicin, pirirubicin, idarubicin, valrubicin, amrubicin, Bleomycin, phleomycin, dactinomycin, Mithramycin, streptozotecin, pentostatin, Mitosanes mitomycin C, Enediynes calicheamycin, Glycosides rebeccamycin, Macrolide lactones epotihilones, ixabepilone, pentostatin, Salinosporamide A, Vinblastine, Vincristine, Etoposide, Teniposide, Vinorelbine, Docetaxel, Camptothecin, Hycamtin, Pederin, Theopederins, Annamides, Trabectedin, Aplidine, and Ecteinascidin 743 (ET743). 
     
     
         40 . The pharmaceutical composition of  claim 37 , wherein the small molecule is Amphotericin B or Doxorubicin. 
     
     
         41 . A pharmaceutical composition comprising a nanocomplex, wherein the nanocomplex is formed of a compound of  claim 17  , and a small molecule; wherein the nanocomplex has a particle size of 50 nm to 1000 nm, and the compound binds to the small molecule via a non-covalent interaction, a covalent bond, or both. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the small molecule is an antifungal agent or a chemotherapeutic agent. 
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein the small molecule is selected from the group consisting of Bortezomib, Imatinib, Gefitinib, Erlotinib, Afatinib, Osimertinib, Dacomitinib, Daunorubicin hydrochloride, cytarabine, Fluorouracil, Irinotecan Hydrochloride, Vincristine Sulfate, Methotrexate, Paclitaxel, Vincristine Sulfate, epirubicin, docetaxel, Cyclophosphamide, Carboplatin, Lenalidomide, Ibrutinib, Abiraterone acetate, Enzalutamide, Pemetrexed, Palbociclib, Nilotinib, Everolimus, Ruxolitinib, epirubicin, pirirubicin, idarubicin, valrubicin, amrubicin, Bleomycin, phleomycin, dactinomycin, Mithramycin, streptozotecin, pentostatin, Mitosanes mitomycin C, Enediynes calicheamycin, Glycosides rebeccamycin, Macrolide lactones epotihilones, ixabepilone, pentostatin, Salinosporamide A, Vinblastine, Vincristine, Etoposide, Teniposide, Vinorelbine, Docetaxel, Camptothecin, Hycamtin, Pederin, Theopederins, Annamides, Trabectedin, Aplidine, and Ecteinascidin 743 (ET743). 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein the small molecule is Amphotericin B or Doxorubicin. 
     
     
         45 . A method of treating a medical condition, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of  claim 37 . 
     
     
         46 . A method of treating a medical condition, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of  claim 41 .