Polycationic methyl phospholipids for improved delivery of nucleic acids to eukaryotic cells

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each X independently is selected from —O—, —OC(O)O—, —C(O)O—, —O(O)C—, —N(R 2 )C(O)O—, —C(O)N(R 2 )—, —OC(O)N(R 2 )—, and —(R 2 )NCON(R 2 )—,

wherein each R 2 is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Y is independently (C 1 -C 6 )alkyl;

each R is independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted arylalkyl, wherein each R group is optionally independently substituted by 1-3 substituent groups, each substituent group independently selected from amino, hydroxyl, (CH 2 ) j OR 11 , (CH 2 ) j C(O)R 11 , (CH 2 ) j C(O)OR 11 , (CH 2 ) j OC(O)R 11 , (CH 2 ) j NR 12 R 13 , (CH 2 ) j C(O)NR 12 R 13 , (CH 2 ) j OC(O)NR 12 R 13 , (CH 2 ) j N 14 RC(O)R 11 , (CH 2 ) j N 14 RC(O)OR 11 , (CH 2 ) j N 14 RC(O)NR 12 R 13 , and (CH 2 ) j N 14 RC(NH)NR 12 R 13 , wherein each j is independently an integer selected from 0 to 6;

R 1 is independently selected from alkyl, (CH 2 ) j OR 11 , (CH 2 ) j C(O)R 11 , and CH 2 CH(OH)CH 2 (OH); and

R 3 is independently selected from H, (CH 2 ) j NR 12 R 13 , C(O)CH[(CH 2 ) 3 NH(CH 2 ) 3 NH 2 ]—[NH(CH 2 ) 3 NH 2 ], C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , C(O)CH(NH 2 )(CH 2 )(C 3 H 3 N 2 ), C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; C(O)CH(NH 2 )CH 2 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 2 NH 2 , and —C(O)CH(NH 2 )CHOH,

wherein R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, and cycloalkyl, where the alkyl or alkenyl is optionally substituted with one or more substituent selected from the group consisting of amino, primary amino, secondary amino, hydroxy, alkoxy, and hydroxyalkyl.

2. The compound of claim 1 , wherein:

each X independently is selected from —O—, —C(O)O—, —O(O)C—, —N(R 2 )C(O)O—, —C(O)N(R 2 )—, —OC(O)N(R 2 )—, and —(R 2 )NCON(R 2 )—;

Y is independently (C 1 -C 4 )alkyl;

each R is independently selected from substituted or unsubstituted (C 1 -C 20 )alkyl, substituted or unsubstituted (C 2 -C 20 )alkenyl, and substituted or unsubstituted (C 2 -C 20 )alkynyl;

R 1 is independently selected from (C 1 -C 6 )alkyl, C(O)R 11 , and CH 2 CH(OH)CH 2 (OH);

R 2 is independently selected from hydrogen and (C 1 -C 4 )alkyl;

R 3 is independently selected from —(CH 2 ) j NH 2 , —C(O)CH[(CH 2 ) 3 NH(CH 2 ) 3 NH 2 ]—[NH(CH 2 ) 3 NH 2 ], C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; —C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 )(C 3 H 3 N 2 ), —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 , —C(O)CH(NH 2 )CH 2 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 2 NH 2 , and —C(O)CH(NH 2 )CHOH;

R 11 is independently selected from hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, trifluoromethyl, and (C 3 -C 8 )cycloalkyl.

3. The compound of claim 2 , wherein:

each X independently is selected from —C(O)O—, —O(O)C—, and —C(O)N(R 2 )—;

Y is independently (C 2 -C 3 )alkyl;

each R is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, and (C 2 -C 20 )alkynyl;

R 1 is independently selected from (C 1 -C 6 )alkyl, C(O)R 11 , and CH 2 CH(OH)CH 2 (OH);

R 2 is independently selected from hydrogen and (C 1 -C 2 )alkyl; and

R 3 is independently selected from —(CH 2 ) j NH 2 , —C(O)CH[(CH 2 ) 3 NH(CH 2 ) 3 NH 2 ]—[NH(CH 2 ) 3 NH 2 ], —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; —C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 )(C 3 H 3 N 2 ), —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 , —C(O)CH(NH 2 )CH 2 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 2 NH 2 , and —C(O)CH(NH 2 )CHOH; and

R 11 is independently selected from hydrogen and (C 1 -C 6 )alkyl.

4. The compound of claim 3 , wherein:

each X independently is selected from —C(O)O— and —O(O)C—;

Y is independently CH 2 CH 2 ;

each R is independently selected from (C 2 -C 20 )alkyl and (C 2 -C 20 )alkenyl;

R 1 is independently selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 3 , —C(CH 3 ) 3 , —C(O)CH 3 , —C(O)CH 2 CH 3 , —C(O)CH 2 CH 2 CH 3 , —C(O)CH(CH 3 ) 2 , —C(O)CH 2 CH 2 CH 2 CH 3 , —C(O)CH 2 CH(CH 3 )CH 3 , —C(O)C(CH 3 ) 3 , and —CH 2 CH(OH)CH 2 (OH); and

R 3 is independently selected from —(CH 2 ) j NH 2 , —C(O)CH[(CH 2 ) 3 NH(CH 2 ) 3 NH 2 ]—[NH(CH 2 ) 3 NH 2 ], —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; —C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 )(C 3 H 3 N 2 ), —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 , —C(O)CH(NH 2 )CH 2 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 2 NH 2 , and —C(O)CH(NH 2 )CHOH.

5. The compound of claim 4 , wherein:

each X independently is selected from —C(O)O— and —O(O)C—;

Y is independently CH 2 CH 2 ;

each R is independently selected from (C 2 -C 20 )alkyl and (C 2 -C 20 )alkenyl;

R 1 is independently selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 )CH 3 , —C(CH 3 ) 3 and —CH 2 CH(OH)CH 2 (OH); and

R 3 is independently selected from —(CH 2 ) j NH 2 , —C(O)CH[(CH 2 ) 3 NH(CH 2 ) 3 NH 2 ]—[NH(CH 2 ) 3 NH 2 ], —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 ; —C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 )(C 3 H 3 N 2 ), —C(O)CH(NH 2 )(CH 2 ) 3 NH 2 , —C(O)CH(NH 2 )CH 2 NH 2 , —C(O)CH(NH 2 )(CH 2 ) 2 NH 2 , and —C(O)CH(NH 2 )CHOH.

6. The compound of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

7. A composition comprising a compound of Formula of claim 1 and one or more compounds selected from the group consisting of:

i) at least one or more neutral lipids;

ii) at least one or more cationic lipids, and/or at least one or more neutral lipids;

iii) one or more polyamine transfection agents;

iv) one or more fusion agents;

v) one or more cell surface ligands;

vi) and one or more nuclear localization peptides or one or more protein cell surface ligands;

vii) and one or more amphipathic peptides;

viii) one or more nuclear localization peptides or one or more protein cell surface ligands, further comprising one or more cationic lipids and/or one or more neutral lipids and/or one or more fusion agents and/or one or more cell surface ligands and one/or more amphipathic peptides;

ix) one or more nuclear localization peptides or one or more protein cell surface ligands, further comprising one or more cationic lipids and/or one or more neutral lipids and/or one or more fusion agents and/or one or more cell surface ligands and one/or more amphipathic peptides wherein the one or more nuclear localization peptides or the one or more protein cell surface ligands comprises a polycationic nucleic acid binding moiety and wherein further the one or more amphipathic peptides are selected from:

(SEQ ID NO: 10)

FEAALAEALAEALA , 

(SEQ ID NO: 11)

Ac- LARLLPRLLARL -NHCH3 ,

(SEQ ID NO: 12)

GLLEELLELLEELWEELLEG ,

(SEQ ID NO: 13)

GWEGLIEGIEGGWEGLIEG ,

(SEQ ID NO: 14)

GLFEALAEFIEGGWEGLIEG , 

(SEQ ID NO: 15)

GLFEALLELLESLWELLLEA , 

(SEQ ID NO: 16)

GGYCLEKWMIVASELKCFGNTA ,

(SEQ ID NO: 17)

GGYCLTRWMLIEAELKCFGNTAV , 

and

(SEQ ID NO: 18)

WEAALAEALAEALAEHLAEALAEALEALAA ;

x) one or more neutral lipids and/or one or more cationic lipids and one or more of the following peptides: GYSTPPKKKRKVEDP (SEQ ID NO:1), GYSTPPKTRRRP (SEQ ID NO:2), GYSTPGRKKR (SEQ ID NO:3), GYSTPRRNRRRRW (SEQ ID NO:4), PDEVKRKKKPPTSYG (SEQ ID NO:5), PRRRTKPPTSYG (SEQ ID NO:6), RKKRGPTSYG (SEQ ID NO:7), WRRRRNRRPTSYG (SEQ ID NO:8), GYGPPKKKRKVEAPYKA(K) 8-40 K (SEQ ID NO:9), FEAALAEALAEALA (SEQ ID NO:10), Ac-LARLLPRLLARL-NHCH3 (SEQ ID NO:11), GLLEELLELLEELWEELLEG (SEQ ID NO:12), GWEGLIEGIEGGWEGLIEG (SEQ ID NO:13), GLFEALAEFIEGGWEGLIEG (SEQ ID NO:14), GLFEALLELLESLWELLLEA (SEQ ID NO:15), GGYCLEKWMIVASELKCFGNTA (SEQ ID NO:16), GGYCLTRWMLIEAELKCFGNTAV (SEQ ID NO:17), WEAALAEALAEALAEHLAEALAEALEALAA (SEQ ID NO:18), INIGTTGWGDHYSLY (SEQ ID NO:19), AARSPSYYRYDYGPYYAMDYD (SEQ ID NO:20), GKWERKPIRCAS (SEQ ID NO:20), GACSERSMNFCG (SEQ ID NO:21), GACYGLPHKFCG (SEQ ID NO:22), YYCQQRSSYPYTFGG (SEQ ID NO:23), TRQARRNRRRRWRERQRGSGSG (SEQ ID NO:24), RDWSSQHPGRCNGETHLK (SEQ ID NO:25), GGGDYYCAAWDDSLNGYSVF (SEQ ID NO:26), VIVTGGDYSFALPVGQWPVMTGGA (SEQ ID NO:27), DKPSYQFGGHNSVDFEEDTLPKV (SEQ ID NO:28), HLRRLRRRLLREAEG (SEQ ID NO:29), and YYCARSGYYAMDYWGQGT (SEQ ID NO:30); and

xi) one or more nucleic acids.

8. The composition of claim 7 , wherein the one or more neutral lipids is selected from DOPE, DPhPE, cholesterol, DOPC, Lyso-PE (1-acyl-2-hydroxy-sn-glycero-3-phospho-ethanolamine), Lyso-PC (1-acyl-3-hydroxy-sn-glycero-3-phosphocholine), and 3-alkoxy-2-hydroxy-1-acetamidopropane.

9. The composition of claim 7 , wherein the cationic lipid is selected from GeneIn™, LipofectAmine™ 2000, LipofectAmine™, Lipofectin®, DMRIE-C, CellFectin® (Invitrogen), Oligofectamine® (Invitrogen), LipofectAce® (Invitrogen), Fugene® (Roche, Basel, Switzerland), Fugene® HD (Roche), Transfectam® (Tranfectam, Promega, Madison, Wis.), Tfx-10® (Promega), Tfx-20® (Promega), Tfx-50® (Promega), Transfectin™ (BioRad, Hercules, Calif.), SilentFect™ (Bio-Rad), Effectene® (Qiagen, Valencia, Calif.), DC-chol (Avanti Polar Lipids), GenePorter® (Gene Therapy Systems, San Diego, Calif.), DharmaFect 1® (Dharmacon, Lafayette, Colo.), DharmaFect 2® (Dharmacon), DharmaFect 3° (Dharmacon), DharmaFect 4® (Dharmacon), Escort™ III (Sigma, St. Louis, Mo.), Escort™ IV (Sigma), DOTMA, DOTAP, DMRIE, DC-Chol, DDAB, DOSPA, DOSPER, DOGS, TMTPS, TMTOS, TMTLS, TMTMS, TMDOS, N-1-dimethyl-N-1-(2,3-diaoleoyloxypropyl)-2-hydroxypropane-1,3-diamine, N-1-dimethyl-N-1-(2,3-diamyristyloxypropyl)-2-hydroxypropane-1,3-diamine, N-1-dimethyl-N-1-(2,3-diapalmityloxy-propyl)-2-hydroxypropane-1,3-diamine, N-1-dimethyl-N-1-(2,3-diaoleoyl-oxypropyl)-2-(3-amino-2-hydroxypropyloxy)propane-1,3-diamine, N-1-dimethyl-N-1-(2,3-diamyristyloxy-propyl)-2-(3-amino-2-hydroxypropyloxy)propane-1,3-diamine, N-1-dimethyl-N-1-(2,3-diapalm-ityloxypropyl)-2-(3-amino-2-hydroxypropyloxy)propane-1,3-diamine, L-spermine-5-carboxyl-3-(DL-1,2-dipalmitoyl-dimethylaminopropyl-β-hydroxyethylamine, 3,5-(N,N-di-lysyl)-diamino-benzoyl-glycyl-3-(DL-1,2-dipalmitoyl-dimethylaminopropyl-β-hydroxyethylamine), L-Lysine-bis(O,O′-oleoyl-β-hydroxy-ethyl)amidedihydrochloride, L-Lysine-bis-(O,O′-palmitoyl-β-hydroxyethyl)amidedihydrochloride, 1,4-bis[(3-(3-aminopropyl)-alkylamino)-2-hydroxypropyl)-piperazine, L-Lysine-bis-(O,O′-myristoyl-β-hydroxyethyl)amide dihydrochloride, L-Ornithine-bis-(O,O′-myristoyl-β-hydroxyethyl)amide dihydrochloride, L-Ornithine-bis-(O,O′-oleoyl-β-hydroxyethyl)amide dihydrochloride, 1,4-bis[(3-(3-aminopropyl)-oleylamino)-2-hydroxy-propyl]piperazine, L-Ornithine-bis-(O,O′-palmitoyl-β-hydroxyethyl)amide dihydrochloride, 1,4,-bis[(3-amino-2-hydroxypropyl)-oleylamino]-butane-2,3-diol, 1,4,-bis[(3-amino-2-hydroxy-propyl)-palmitylamino]-butane-2,3-diol, 1,4,-bis[(3-amino-2-hydroxypropyl)-myristylamino]-butane-2,3-diol, 1,4-bis[(3-oleylamino)propyl]-piperazine, L-Arginine-bis-(O,O′-oleoyl-β-hydroxyethyl)amide dihydrochloride, bis[(3-(3-aminopropyl)-myristylamino)2-hydroxy-propyl]piperazine, L-Arginine-bis-(O,O′-palmitoyl-β-hydroxyethyl)amide dihydrochloride, L-Serine-bis-(O,O′-oleoyl-β-hydroxyethyl)amide dihydrochloride, 1,4-bis[(3-(3-aminopropyl)-palmitylamino)-2-hydroxypropyl]piperazine, Glycine-bis-(O,O′-palmitoyl-β-hydroxy-ethyl)amide dihydrochloride, Sarcosine-bis-(O,O′-palmitoyl-β-hydroxyethyl)amide dihydrochloride, L-Histidine-bis-(O,O′-palmitoyl-β-hydroxyethyl)amide dihydrochloride, cholesteryl-3β-carboxyl-amidoethylenetrimethylammonium iodide, 1,4-bis[(3-myristyl-amino)-propyl]-piperazine, 1-dimethylamino-3-trimethylammonio-DL-2-propyl-cholesteryl carboxylate iodide, cholesteryl-3β-carboxyamidoethyleneamine, cholesteryl-3β-oxysuccinamido-ethylene-trimethylammonium iodide, 1-dimethylamino-3-trimethylammonio-DL-2-propyl-cholesteryl-3β-oxysuccinate iodide, 2-[(2-trimethylammonio)-ethylmethyl-amino]ethyl-cholesteryl-3β-oxysuccinate iodide, 3β[N—(N′,N′-dimethylamino-ethane)-carbamoyl]cholesterol, and 3β-[N-(polyethyleneimine)-carbamoyl]cholesterol, 1,4-bis[(3-palmitylamino)propyl]piperazine, L-Ornithylglycyl-N-(1-heptadecyloctadecyl)-glycinamide, N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl-glycyl-N-(1-heptadecyloctadecyl)-glycinamide, 1,4-bis[(3-(3-amino-2-hydroxypropyl)-alkylamino)-2-hydroxypropyl]-piperazine, N 2 —[N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl]-N,N-dioctadecyl-L-glutamine, N 2 —[N 2 ,N 5 -Bis(aminopropyl)-L-ornithyl]-N—N-dioctadecyl-L-α-glutamine, 1,4-bis[(3-(3-amino-2-hydroxypropyl)-oleylamino)2-hydroxypropyl]piperazine, N 2 —[N 2 ,N 5 -Bis(amino-propyl)-L-ornithyl]-N—N-dioctadecyl-L-α-asparagine, N—[N 2 —[N 2 ,N 5 -Bis[(1,1-dimethyl-ethoxy)carbonyl]-N 2 ,N 5 -bis[3-[(1,1-dimethylethoxy)carbonyl]aminopropyl]-L-ornithyl-N—N-dioctadecyl-L-glutaminyl]-L-glutamic acid, N 2 —[N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl]-N,N-diolyl-L-glutamine, N 2 —[N 2 ,N 5 -Bis(aminopropyl)-L-ornithyl]-N—N-dioleyl-L-α-glutamine, 4-bis[(3-(3-amino-2-hydroxypropyl)-myristylamino)-2-hydroxy-propyl]piperazine, N 2 —[N 2 ,N 5 -Bis(aminopropyl)-L-ornithyl]-N—N-dioleyl-L-α-asparagine, N—[N 2 —[N 2 ,N 5 -Bis[(1,1-dimethylethoxy)carbonyl]-N 2 ,N 5 -bis[3-[(1,1-dimethylethoxy)carbonyl]aminopropyl]-L-ornithyl-N—N-dioleyl-L-glutaminyl]-L-glutamic acid, 1,4-bis[(3-(3-aminopropyl)-oleyl-amino)-propyl]piperazine, N 2 —[N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl]-N,N-dipalmityl-L-glutamine, N 2 —[N 2 ,N 5 -Bis(amino-propyl)-L-ornithyl]-N—N-dipalmityl-L-α-glutamine, N 2 —[N 2 ,N 5 -Bis(amino-propyl)-L-ornithyl]-N—N-dipalmityl-L-α-asparagine, N—[N 2 —[N 2 ,N 5 -Bis[(1,1-dimethylethoxy)-carbonyl]-N 2 ,N 5 -bis[3-[(1,1-dimethylethoxy)carbonyl]aminopropyl]-L-ornithyl-N—N-dipalmityl-L-glutaminyl]-L-glutamic acid, N 2 —[N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl]-N,N-dimyristyl-L-glutamine, N 2 —[N 2 ,N 5 -Bis(aminopropyl)-L-ornithyl]-N—N-dimyristyl-L-α-glutamine, N 2 —[N 2 ,N 5 -Bis(aminopropyl)-L-ornithyl]-N—N-dimyristyl-L-α-asparagine, 1,4-bis[(3-(3-amino-2-hydroxy-propyl)-palmitylamino)-2-hydroxypropyl]-piperazine, N—[N 2 —[N 2 ,N 5 -Bis[(1,1-dimethyl-ethoxy)carbonyl]-N 2 ,N 5 -bis[3-[(1,1-dimethylethoxy)carbonyl]aminopropyl]-L-ornithyl-N—N-dimyristyl-L-glutaminyl]-L-glutamic acid, 1,4-bis[(3-(3-aminopropyl)-myristyl-amino)-propyl]piperazine, N 2 —[N 2 ,N 5 -Bis(3-aminopropyl)-L-ornithyl]-N,N-dilaureyl-L-glutamine, N 2 —[N 2 ,N 5 -Bis(amino-propyl)-L-ornithyl]-N—N-dilaureyl-L-α-glutamine, N 2 —[N 2 ,N 5 Bis-(amino-propyl)-L-ornithyl]-N—N-dilaureyl-L-α-asparagine, N—[N 2 —[N 2 ,N 5 -Bis[(1,1-dimethylethoxy)-carbonyl]-N 2 ,N 5 -bis[3-[(1,1-dimethylethoxy)carbonyl]aminopropyl]-L-ornithyl-N—N-dilaureyl-L-glutaminyl]-L-glutamic acid, 3-[N′,N″-bis(2-tertbutyloxycarbonyl-amino-ethyl)guanidino]-N,N-dioctadec-9-enylpropionamide, 3-[N′,N″-bis(2-tertbutyloxy-carbonylamino-ethyl)guanidino]-N,N-dipalmitylpropionamide, 3-[N′,N″-bis(2-tertbutyl-oxycarbonyl-aminoethyl)guanidino]-N,N-dimyristylpropionamide, 1,4-bis[(3-(3-amino-propyl)-palmityl-amino)propyl]piperazine, 1,4-bis[(3-(3-amino-2-hydroxypropyl)-oleyl-amino)propyl]piperazine, N,N-(2-hydroxy-3-aminopropyl)-N-2-hydroxypropyl-3-N,N-diolylaminopropane, N,N-(2-hydroxy-3-aminopropyl)-N-2-hydroxypropyl-3-N,N-dipalmitylaminopropane, N,N-(2-hydroxy-3-aminopropyl)-N-2-hydroxypropyl-3-N,N-dimyristylaminopropane, 1,4-bis[(3-(3-amino-2-hydroxypropyl)-myristylamino)-propyl]piperazine, [(3-aminopropyl)-bis-(2-tetradecyl-oxyethyl)]methyl ammonium bromide, [(3-aminopropyl)-bis-(2-oleyloxyethyl)]methyl ammonium bromide, [(3-aminopropyl)-bis-(2-palmityloxyethyl)]methyl ammonium bromide, oleoyl-2-hydroxy-3-N,N-dimethyamino propane, 2-didecanoyl-1-N,N-dimethylaminopropane, palmitoyl-2-hydroxy-3-N,N-dimethyamino propane, 1,2-dipalmitoyl-1-N,N-dimethylamino-propane, myristoyl-2-hydroxy-3-N,N-dimethyamino propane, 1,2-dimyristoyl-1-N,N-dimethylaminopropane, (3-amino-propyl)→4-(3-amino-propylamino)-4-tetradecyl-carbamoyl-butylcarbamic acid cholesteryl ester, (3-Amino-propyl)→4-(3-amino-propylamino-4-carbamoylbutylcarbamic acid cholesteryl ester, (3-Amino-propyl)→4-(3-amino-propylamino)-4-(2-dimethylamino-ethylcarbamoyl-1)-butylcarbamic acid cholesteryl ester, Spermine-5-carboxyglycine (N′-stearyl-N′-oleyl) amide tetratrifluoro-acetic acid salt, Spermine-5-carboxyglycine (N′-stearyl-N′-elaidyl) amide tetratri-fluoroacetic acid salt, Agmatinyl carboxycholesterol acetic acid salt, Spermine-5-carboxy-β-alanine cholesteryl ester tetratrifluoroacetic acid salt, 2,6-Diaminohexanoeyl β-alanine cholesteryl ester bistrifluoroacetic acid salt, 2,4-Diaminobutyroyl β-alanine cholesteryl ester bistrifluoroacetic acid salt, N,N-Bis (3-aminopropyl)-3-aminopropionyl β-alanine cholesteryl ester tristrifluoroacetic acid salt, [N,N-Bis(2-hydroxyethyl)-2-aminoethyl]aminocarboxy cholesteryl ester, Stearyl carnitine ester, Palmityl carnitine ester, Myristyl carnitine ester, Stearyl stearoyl carnitine ester chloride salt, L-Stearyl Stearoyl Carnitine Ester, Stearyl oleoyl carnitine ester chloride, Palmityl palmitoyl carnitine ester chloride, Myristyl myristoyl carnitine ester chloride, L-Myristyl myristoyl carnitine ester chloride, 1,4-bis[(3-(3-amino-2-hydroxypropyl)-palmityl-amino)propyl]-piperazine, N-(3-aminopropyl)-N,N′-bis-(dodecyloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N,N′-bis-(oleyloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N,N′-bis-(palmityloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N,N′-bis-(myristyloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N′-methyl-N,N′-(bis-2-dodecyloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N′-methyl-N,N′-(bis-2-oleyloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N′-methyl-N,N′-(bis-2-palmityloxyethyl)-piperazinium bromide, N-(3-aminopropyl)-N′-methyl-N,N′-(bis-2-myristyloxyethyl)-piperazinium bromide, 1,4-bis[(3-(3-aminopropyl)-oleylamino)-2-hydroxy-propyl]piperazine, 1,4-bis[(3-(3-aminopropyl)-myristylamino)-2-hydroxy-propyl]piperazine, or 1,4-bis[(3-(3-aminopropyl)-palmitylamino)-2-hydroxypropyl]-piperazine, 2,3-dioleyloxy-1,4-N,N′-dimethyl-N,N′-di(2-hydroxy-3-aminopropyl)-diaminobutane, 2,3-dipalmitoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(2-hydroxy-3-amino-propyl)-diaminobutane, 2,3-dimyristoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(2-hydroxy-3-aminopropyl)-diaminobutane, 2,3-dioleyloxy-1,4-N,N′-dimethyl-N,N′-di(3-amino-propyl)-diaminobutane, 2,3-dipalmitoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(3-amino-propyl)-diamino-butane, 2,3-dimyristoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(3-amino-propyl)-diaminobutane, 2,3-dioleyloxy-1,4-N,N′-dimethyl-N,N′-di(5-carboxamido-spermine)-diaminobutane, 2,3-dipalm-itoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(5-carboxamidospermine)-diaminobutane, 2,3-dimyrist-oleoyloxy-1,4-N,N′-dimethyl-N,N′-di(5-carboxamidospermine)-diaminobutane, 2,3-dioleyloxy-1,4-N,N′-dimethyl-N,N′-di(lysyl)-diaminobutane, 2,3-dipalmitoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(lysyl)-diaminobutane, 2,3-dimyristoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(lysyl)-diamino-butane, 2,3-dioleyloxy-1,4-N,N′-dimethyl-N,N′-di(histidyl)-diaminobutane, 2,3-dipalmitoleoyl-oxy-1,4-N,N′-dimethyl-N,N′-di(histidyl)-diaminobutane, 2,3-dimyristoleoyloxy-1,4-N,N′-dimethyl-N,N′-di(histidyl)-diaminobutane, 2,3-dioleyloxy-N,N′-dimethyl-1,4-diaminobutane, 2,3-dipalmitoleoyloxy-N,N′-dimethyl-1,4-diaminobutane, 2,3-dimyrist-oleoyloxy-N,N′-dimethyl-1,4-diaminobutane; PAMAM dendrimers, NH 3 core dendrimers, ethylenediamine core dendrimers, polyethylenimine, and polyethylenimine conjugates.

10. The composition of claim 7 , wherein the one or more neutral lipids is selected from DOPE, DPhPE, cholesterol, DOPC, Lyso-PE (1-acyl-2-hydroxy-sn-glycero-3-phospho-ethanolamine), Lyso-PC (1-acyl-3-hydroxy-sn-glycero-3-phosphocholine), and 3-alkoxy-2-hydroxy-1-acetamidopropane.

11. The composition of claim 10 , wherein the alkyl group of the alkoxy is selected from oleyl, palmityl, palmitoleoyl, myristoyl, myristyl, and lauryl.

12. The composition of claim 7 , wherein the one or more polyamine transfection agents is selected from dense star dendrimers, PAMAM dendrimers, NH 3 core dendrimers, ethylenediamine core dendrimers, dendrimers of generation 5 or higher, dendrimers with substituted groups, dendrimers comprising one or more amino acids, grafted dendrimers, activated dendrimers, polyethylenimine, polyethylenimine conjugates, polylysine, polyarginine, polyornithine, and histone.

13. The composition of claim 7 , wherein the one or more fusion agents comprises a polycationic nucleic acid binding moiety.

14. The composition of claim 7 , further comprising one or more cationic lipids and/or one or more neutral lipids.

15. The composition of claim 7 , wherein the one or more cell surface ligands comprises a polycationic nucleic acid binding moiety.

16. The composition of claim 7 , wherein the one or more nuclear localization peptides or the one or more protein cell surface ligands comprises a polycationic nucleic acid binding moiety.

17. The composition of claim 7 , further comprising one or more cationic lipids and/or one or more neutral lipids and/or one or more fusion agents and/or one or more cell surface ligands.

18. The composition of claim 7 , wherein the one or more amphipathic peptides are selected from: FEAALAEALAEALA (SEQ ID NO:10), Ac-LARLLPRLLARL-NHCH3 (SEQ ID NO:11), GLLEELLELLEELWEELLEG (SEQ ID NO:12), GWEGLIEGIEGGWEGLIEG (SEQ ID NO:13), GLFEALAEFIEGGWEGLIEG (SEQ ID NO:14), GLFEALLELLESLWELLLEA (SEQ ID NO:15), GGYCLEKWMIVASELKCFGNTA (SEQ ID NO:16), GGYCLTRWMLIEAELKCFGNTAV (SEQ ID NO:17), and WEAALAEALAEALAEHLAEALAEALEALAA (SEQ ID NO:18).

19. The composition of claim 7 , wherein the one or more amphipathic peptides is covalently linked to a polycationic nucleic binding moiety.

20. The compositions of claim 7 , the peptide is covalently linked to a nucleic acid binding moiety.

21. The composition of claim 7 , wherein the one or more nucleic acids are selected from DNA and RNA.

22. The composition of claim 21 , wherein the RNA is and RNAi molecule.

23. A method of introducing a nucleic acid, protein, or peptide into a eukaryotic cell, comprising contacting the cell with a composition of claim 6 , thereby introducing the nucleic acid, protein, or peptide into the cell.

24. A method of expressing a protein in a cell, comprising contacting the cell with an expression vector encoding the protein and (i) a compound of claim 1 or (ii) the composition of claim 6 , wherein the expression vector is internalized within the cell, and the encoded protein is expressed.

25. A method of inhibiting expression of a protein in a cell, comprising contacting the cell with an RNAi molecule and (i) a compound of claim 1 or (ii) the composition of claim 6 , wherein the RNAi molecule is internalized within the cell and expression of the protein is thereby reduced.