Functionally-modified oligonucleotides and subunits thereof

1. A compound having the structure of Formula (I):

or a salt or isomer thereof,

wherein:

n is an integer from 1 to 50;

G 5 is halogen, OH, alkoxy, OSO 2 (alkyl), OSO 2 (aryl), or

each B is an independently selected base pair moiety;

each Y is independently O or NR 10 ; optionally, R 10 and X8e are bonded together form a ring;

each W is independently S or O;

Z 5 is -(L 11 )-(R 15 ), -(L 11 )-(L 15 )-(R 16 ), or -(L 11 )-(L 12 )-(R 17 );

L 11 is selected from:

wherein L 13 is selected from:

L 12 is a linker cleaveable under biological conditions selected from:

a) —(C 1 -C 10 alkylene)-OC(O)O—CH 2 O—;

b) —C(O)—(C 1 -C 10 alkylene)-OC(O)O—CH 2 O—;

c) —C(O)—(CH═CH)—C(O)O—CH 2 O—;

d) —(C 1 -C 10 alkylene)-S—S—CH 2 CH 2 O—; or

e) —C(O)—(C 1 -C 10 alkylene)-S—S—CH 2 CH 2 O—;

L 15 is divalent radical selected from C 1 -C 30 alkylene, C 3 -C 8 cycloalkylene, C 6 -C 30 arylene, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-, —(C 1 -C 30 alkylene)-C(═O)—, —(C 2 -C 30 alkoxy)-C(═O)—, -(3-18 membered heteroalkylene)-C(═O)—, —(C 3 -C 8 cycloalkylene)-C(═O)—, —(C 3 -C 8 cycloalkylene)-(C 1 -C 30 alkylene)-C(═O)—, —(C 1 -C 30 alkylene) (C 3 -C 8 cycloalkylene)-C(═O)—, —(C 6 -C 30 arylene)-C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-C(═O)—, —(C 1 -C 30 alkylene)-(C 6 -C 30 arylene)-C(═O)—, —(C 1 -C 30 alkylene)-O—C(═O)—, —(C 3 -C 8 cycloalkylene)-O—C(═O)—, —(C 7 -C 30 arylene)-O—C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-O—C(═O)—, —(C 6 -C 30 arylene)-(C 1 -C 30 alkylene)-O—C(═O)—, —C(═O)OR 21 , or —P(═O)(R 22 ) 2 ;

R 12 is an electron pair, with the provision that if R 13 is C 1 -C 30 alkyl, then R 12 is an electron pair, an N-oxide, or C 1 -C 6 alkyl;

each R 10 and R 13 is independently selected from hydrogen, a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 1 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 6 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 1 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, —C(═O)OR 21 , —C(═O)NHR 21 , or —P(═O)(R 22 ) 2 ;

R 15 is independently selected from a cell-penetrating peptide, a natural or non-natural amino acid, guanidinyl, amidinyl, heterocyclyl, C 1 -C 30 alkyl, C 3 -C 8 cycloalkyl; C 6 -C 30 aryl, C 7 -C 30 aralkyl, C 1 -C 30 alkylcarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkylalkylcarbonyl, C 6 -C 30 arylcarbonyl, C 7 -C 30 aralkylcarbonyl, C 2 -C 30 alkyloxycarbonyl, C 3 -C 8 cycloalkyloxycarbonyl, C 7 -C 30 aryloxycarbonyl, C 8 -C 30 aralkyloxycarbonyl, 3-18 membered alkoxyalkylcarbonyl, —SO 2 R 21 , —C(═O)OR 21 , —P(═O)(OH) 2 or —P(═O)(R 22 ) 2 ;

R 16 is a solid support matrix suitable for solid phase synthesis of oligonucleotides;

R 17 is a drug, protein or toxin;

each R 21 is independently C 1 -C 30 alkyl, or a 3-18 membered alkoxyalkyl group;

each R 22 is independently an C 6 -C 12 aryloxy;

each R 23 is independently H or C 1 -C 6 alkyl; or optionally two R 23 groups join to form a 3- to 8-membered ring;

R 24 is a C 1 -C 6 alkylene;

Q is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8;

each X is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8 with the provision that at least one X is not X1;

wherein

X1 is N(CH 3 ) 2 ;

X2 is selected from:

a) —O-alkylene-CO 2 H;

b) —O-alkylene-CHN 4 ;

c) —N(R 1 )-alkylene-CO 2 H;

d) —N(R 1 )-alkylene-CHN 4 ;

e) -L1-CO-alkylene-CO 2 H;

f) -L1-CO-alkylene-CHN 4 ;

g) -L1-CO-alkenylene-CO 2 H;

h) -L1-CO-alkenylene-CHN 4 ;

i) -L1-CO-arylene-CO 2 H;

j) -L1-CO-arylene-CHN 4 ;

k) -L1-CONH-alkylene-CO 2 H;

l) -L1-CONH-alkylene-CHN 4 ;

m) -L1-CONH-arylene-CO 2 H;

n) -L1-CONH-arylene-CHN 4 ;

o) -L1-SO 2 -alkylene-CO 2 H;

p) -L1-SO 2 -alkylene-CHN 4 ;

q) -L1-SO 2 -arylene-CO 2 H;

r) -L1-SO 2 -arylene-CHN 4 ;

s) -L1-alkylene-CO 2 H;

t) -L1-alkylene-CHN 4 ;

u) -L1-arylene-CO 2 H;

v) -L1-arylene-CHN 4 ; and

w) a protected form of any of the above X2groups;

X3 is selected from:

a) -L1-alkyl;

b) -L1-heterocyclyl;

c) —O-alkylene-CNH—NH 2 ;

d) —N(R 1 )-alkylene-CNH—NH 2 ;

e) -L1-CNH—NH 2 ;

f) -L1-alkylene-CNH—NH 2 ;

g) -L1-arylene-CNH—NH 2 ;

h) -L1-CO-alkylene-CNH—NH 2 ;

i) -L1-CO-alkenylene-CNH—NH 2 ;

j) -L1-CO-arylene-CNH—NH 2 ;

k) -L1-CONH-alkylene-CNH—NH 2 ;

l) -L1-CONH-arylene-CNH—NH 2 ;

m) -L1-SO 2 -alkylene-CNH—NH 2 ;

n) -L1-SO 2 -arylene-CNH—NH 2 ;

o) —O-alkylene-N(R 1 ) 2 ;

p) —N(R 1 )-alkylene-N(R 1 ) 2 ;

q) -L1-N(R 1 ) 2 ;

r) -L1-alkylene-N(R 1 ) 2 ;

s) -L1-arylene-N(R 1 ) 2 ;

t) -L1-CO-alkylene-N(R 1 ) 2 ;

u) -L1-CO-alkenylene-N(R 1 ) 2 ;

v) -L1-CO-arylene-N(R 1 ) 2 ;

w) -L1-CONH-alkylene-N(R 1 ) 2 ;

x) -L1-CONH-arylene-N(R 1 ) 2 ;

y) -L1-SO 2 -alkylene-N(R 1 ) 2 ;

z) —O-alkylene-N(R 2 ) 3 ;

aa) —N(R 1 )-alkylene-N(R 2 ) 3 ;

bb) -L1-N(R 2 ) 3 ;

cc) -L1-alkylene-N(R 2 ) 3 ;

dd) -L1-arylene-N(R 2 ) 3 ;

ee) -L1-CO-alkylene-N(R 2 ) 3 ;

ff) -L1-CO-alkenylene-N(R 2 ) 3 ;

gg) -L1-CO-arylene-N(R 2 ) 3 ;

hh) -L1-CONH-alkylene-N(R 2 ) 3 ;

ii) -L1-CONH-arylene-N(R 2 ) 3 ;

jj) -L1-SO 2 -alkylene-N(R 2 ) 3 ;

kk) —O-alkylene-heterocyclyl;

ll) —N(R 1 )-alkylene-heterocyclyl;

mm) -L1-alkylene-heterocyclyl;

nn) -L1-arylene-heterocyclyl;

oo) -L1-CO-alkylene-heterocyclyl;

pp) -L1-CO-alkenylene-heterocyclyl;

qq) -L1-CO-arylene-heterocyclyl;

rr) -L1-CONH-alkylene-heterocyclyl;

ss) -L1-CONH-arylene-heterocyclyl;

tt) -L1-SO 2 -alkylene-heterocyclyl;

uu) —O-alkylene-N(O)(R 2 ) 2 ;

vv) —N(R 1 )-alkylene-N(O)(R 2 ) 2 ;

ww) -L1-N(O)(R 2 ) 2 ;

xx) -L1-alkylene-N(O)(R 2 ) 2 ;

yy) -L1-arylene-N(O)(R 2 ) 2 ;

zz) -L1-CO-alkylene-N(O)(R 2 ) 2 ;

aaa) -L1-CO-alkenylene-N(O)(R 2 ) 23 ;

bbb) -L1-CO-arylene-N(O)(R 2 ) 2 ;

ccc) -L1-CONH-alkylene-N(O)(R 2 ) 2 ;

ddd) -L1-CONH-arylene-N(O)(R 2 ) 2 ;

eee) -L1-SO 2 -alkylene-N(O)(R 2 ) 2 ;

fff) —O-alkylene-NH—CNH—NH 2 ;

ggg) —N(R 1 )-alkylene-NH—CNH—NH 2 ;

hhh) -L1-NH—CNH—NH 2 ;

iii) -L1-alkylene-NH—CNH—NH 2 ;

jjj) -L1-arylene-NH—CNH—NH 2 ;

kkk) -L1-CO-alkylene-NH—CNH—NH 2 ;

lll) -L1-CO-alkenylene-NH—CNH—NH 2 ;

mmm) -L1-CO-arylene-NH—CNH—NH 2 ;

nnn) -L1-CONH-alkylene-NH—CNH—NH 2 ;

ooo) -L1-CONH-arylene-NH—CNH—NH 2 ;

ppp) -L1-SO 2 -alkylene-NH—CNH—NH 2 ;

qqq) -L1-SO 2 -arylene-NH—CNH—NH 2 ; and

rrr) a protected form of any of the above X3 groups;

with the provision that if X1 is present as N(CH 3 ) 2 , and X7 is present as piperidinyl, then X3 is not

X4 is selected from:

a) —O-alkylene-aryl;

b) —N(R 1 )-aryl;

c) —N(R 1 )-alkylene-aryl;

d) -L1-CO-alkylene-aryl;

e) -L1-CO-alkenylene-aryl;

f) -L1-CO-arylene-aryl;

g) -L1-CONH-alkylene-aryl;

h) -L1-CONH-arylene-aryl;

i) -L1-SO 2 -alkylene-aryl;

j) -L1-SO 2 -arylene-aryl;

k) -L1-alkylene-aryl;

l) -L1-arylene-aryl;

m) —N(R 1 )-alkylene-N(R 1 )-aryl;

n) —N(R 1 )-alkylene-N(R 1 )CO-aryl;

o) —N(R 1 )-alkylene-N(R 1 )SO 2 -aryl;

p) —N(R 1 )-alkylene-N(R 1 )CH 2 -aryl;

q) -L1-aryl;

r) -L1-CO-aryl;

s) -L1-SO 2 -aryl;

t) -L1-alkylene-P(aryl) 3 ;

u) -L1-CO-alkylene-P(aryl) 3 ;

v) -L1-SO 2 -alkylene-P(aryl) 3 ;and

w) a protected form of any of the above X4 groups;

X5 is selected from:

a) —O-alkylene-heteroaryl;

b) —N(R 1 )-alkylene-heteroaryl;

c) -L1-CO-alkylene-heteroaryl;

d) -L1-CO-alkenylene-heteroaryl;

e) -L1-CO-arylene-heteroaryl;

f) -L1-CONH-alkylene-heteroaryl;

g) -L1-CONH-arylene-heteroaryl;

h) -L1-SO 2 -alkylene-heteroaryl;

i) -L1-SO 2 -arylene-heteroaryl;

j) -L1-alkylene-heteroaryl;

k) -L1-arylene-heteroaryl;

l) —N(R 1 )-alkylene-N(R 1 )-hereroaryl;

m) —N(R 1 )-alkylene-N(R 1 )CO-hereroaryl;

n) —N(R 1 )-alkylene-N(R 1 )SO 2 -hereroaryl;

o) —N(R 1 )-alkylene-N(R 1 )CH 2 -hereroaryl;

p) -L1-heteroaryl; and

q) a protected form of any of the above X5 groups;

X6 is selected from:

a) —O-alkylene-(OCH 2 CH 2 ) m OH;

b) —O-alkylene-(OCH 2 CH 2 ) m OCH 3 ;

c) —N(R 1 )-alkylene-(OCH 2 CH 2 ) m OH;

d) —N(R 1 )-alkylene-(OCH 2 CH 2 ) m OCH 3 ;

e) —N(R 1 )-arylene-(OCH 2 CH 2 ) m OH;

f) —N(R 1 )-arylene-(OCH 2 CH 2 ) m OCH 3 ;

g) -L1-alkylene-(OCH 2 CH 2 ) m OH;

h) -L1-CO-alkylene-(OCH 2 CH 2 ) m OH;

i) -L1-CO-alkylene-(OCH 2 CH 2 ) m OCH 3 ;

j) -L1-SO 2 -alkylene-(OCH 2 CH 2 ) m OH;

k) -L1-SO 2 -alkylene-(OCH 2 CH 2 ) m OCH 3 ;

l) -L1-CO-arylene-(OCH 2 CH 2 ) m OH;

m) -L1-CO-arylene-(OCH 2 CH 2 ) m OCH 3 ;

n) -L1-SO 2 -arylene-(OCH 2 CH 2 ) m OH;

o) -L1-SO 2 -arylene-(OCH 2 CH 2 ) m OCH 3 ;

p) -L1-CO-(OCH 2 CH 2 ) m OH;

q) -L1-CO-(OCH 2 CH 2 ) m OCH 3 ;

r) —N(R 1 )-(dibenzo-18-crown-6);

s) an aza-crown ether; and

t) a protected form of any of the above X6 groups;

X7 is selected from:

a) -heterocyclyl;

b) —N(R 1 )(R 3 )

c) -L1-hydrogen;

d) -L1-alkyl;

e) -L1-CO-alkyl;

f) -L1-CONH-alkyl;

g) -L1-CON(alkyl)-alkyl;

h) -L1-SO 2 -alkyl; and

i) a protected form of any of the above X7groups;

with the provision that if X1 is present as N(CH 3 ) 2 , and X3 is present as

then X7 is not piperdinyl;

X8 is selected from:

a) -L1-CA;

b) -L1-dCA;

c) -L1-COCH 2 (R 4 )

d) -L1-COCH(R 4 )NHCO 2 -alkyl;

e) —OR 5 , wherein R 5 and R 10 together form a ring;

f) a protected form of any of the above X8 groups;

each R 1 is independently hydrogen, alkyl, or a cell-penetrating peptide;

each R 2 is independently C 1 -C 12 alkyl or optionally when two R 2 are C 1 -C 12 alkyl, two R 2 are joined to form a heterocyclic ring;

each R 3 is independently C 2 -C 18 alkyl, alkenyl, or alkynyl;

each R 4 is independently hydrogen, alkyl, hydroxyalkyl, sulfhydrylalkyl, or arylalkyl;

each R 5 is independently C 1 -C 12 alkyl;

each R 6 is independently hydrogen or C 1 -C 12 alkyl;

L1 is selected from:

wherein

each Q 1 and Q 2 are each selected from a bond, —O— or —N(R 6 )—;

each E 1 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;

each E 2 is independently an optionally substituted nitrogen containing heteroaryl;

each L 4 and L 5 are each independently a bond, optionally substituted C 1 -C 6 alkyl, or optionally substituted heteroalkyl; and

m, p, q, s, and t are each independently 1-4,

wherein if the X group proximal to the 3′ terminus is:

then at least three other X group are not X1, and

wherein the compound is not of the formula:

2. The compound of claim 1 , wherein Z 5 is -(L 11 )-(R 15 ); each Y is independently O, NH, or NR 10 ; each W is O; each R 1 is independently hydrogen or alkyl; each R 2 is independently C 1 -C 12 alkyl; and each X is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8.

3. The compound of claim 1 , wherein R 13 is an optionally substituted triphenylmethyl group.

4. The compound of claim 2 , wherein G 5 is

5. The compound of claim 4 , wherein each W is O and each Y is O.

6. The compound of claim 5 , wherein at least one X is selected from:

7. The compound of claim 5 , wherein at least one X is selected from -L1-heterocyclyl, and wherein L1 is selected from:

8. The compound of claim 5 , wherein at least one X is selected from:

9. The compound of claim 5 , wherein at least one X is selected from —N(R 1 )-alkylene-CNH—NH 2 , —N(R 1 )-alkylene-N(R 1 ) 2 , —N(R 1 )-alkylene-N(R 2 ) 3 , —N(R 1 )-alkylene-heterocyclyl, —N(R 1 )-alkylene-N(O)(R 2 ) 2 , and —N(R 1 )-alkylene-NH—CNH—NH 2 .

10. The compound of claim 5 , wherein at least one X is selected from —O-alkylene-aryl, —N(R 1 )-aryl, —N(R 1 )-alkylene-aryl, —N(R 1 )-alkylene-N(R 1 )-aryl, —N(R 1 )-alkylene-N(R 1 )CO-aryl, —N(R 1 )-alkylene-N(R 1 )SO 2 -aryl, and —N(R 1 )-alkylene-N(R 1 )CH 2 -aryl.

11. The compound of claim 5 , wherein at least one X is selected from —O-alkylene-heteroaryl, —N(R 1 )-alkylene-heteroaryl, —N(R 1 )-alkylene-N(R 1 )-heteroaryl, —N(R 1 )-alkylene-N(R 1 )CO-heteroaryl, —N(R 1 )-alkylene-N(R 1 )SO 2 -heteroaryl, and —N(R 1 )-alkylene-N(R 1 )CH 2 -heteroaryl.

12. The compound of claim 5 , wherein at least one X is selected from -L1-heteroaryl, -L1-alkylene-heteroaryl, -L1-arylene-heteroaryl, -L1-CO-alkylene-heteroaryl, -L1-CO-alkenylene-heteroaryl, -L1-CO-arylene-heteroaryl, -L1-CONH-alkylene-heteroaryl, -L1-CONH-arylene-heteroaryl, -L1-SO 2 -alkylene-heteroaryl, -L1-SO 2 -arylene-heteroaryl.

13. The compound of claim 5 , wherein at least one X is -L1-CO-alkyl.

14. The compound of claim 5 , wherein at least one X is X8.

15. The compound of claim 5 , wherein Z 5 is -(L 11 )-(R 15 ) wherein R 15 is selected from —C(═O)OCH 2 CH 2 OH, —C(═O)OCH 2 CH 2 OCH 2 CH 2 OH, or —C(═O)OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OH.

16. The compound of claim 15 , wherein Z 5 is