Compounds having anti-adhesive effects on cancer cells
Compounds of the form O-(x-L)n, where O is an oligonucleoside having at least a plurality of N3′→P5′ thiophosphoramidate (NPS) internucleoside linkages, a conjugated lipid moiety L, and at least one G-rich sequence motif as described, are effective to morphologically alter and reduce adhesion of cancer cells.
1. A compound having a structure represented by o-(x-L) n , where
(a) o is a polynucleoside moiety comprising a sequence of nucleosides and linkage moieties, wherein
(i) at least 50% of said linkage moieties are selected from: 3′-NH—P(O)(S − )-5′; 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′; and 3′-Y—R—O—P(O)(S − )-5′;
and at least 75% of internucleoside linkage moieties are selected from 3′-NH—P(O)(S − )-5′ and 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′;
where Y is NH or O; R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino; and m is 1 to 3;
and
(ii) said polynucleoside moiety includes at least one motif selected from GGG, GGWGG, and GGWWGG, containing residues selected from G and W, where G is guanosine and W is a nucleoside or the moiety —OR—, where R is as defined above, and the inter-residue linkages within said motif are N3′→P5′ thiophosphoramidate (3′-NH—P(O)(S − )-5′) or phosphorothioate (3′-O—P(O)(S − )-5′) linkages;
(b) x is an optional linker group,
(c) L is a lipid moiety comprising a linear hydrocarbon moiety at least 12 carbon atoms in length, and
(d) n is 1 or 2;
wherein the compound o-(x-L) n is not a telomerase inhibitor.
2. The compound of claim 1 , wherein Y is NH.
3. The compound of claim 1 , wherein m is 1.
4. The compound of claim 1 , wherein at least 85% of said internucleoside linkage moieties are selected from 3′-NH—P(O)(S − )-5′ (NPS) and 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′, where m is 1.
5. The compound of claim 1 , wherein said inter-residue linkages are 3′-NH—P(O)(S − )-5′ (NPS) linkages.
6. The compound of claim 1 , wherein all of said internucleoside linkage moieties are selected from 3′-NH—P(O)(S − )-5′ (NPS) linkages and 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′ linkages, where m is 1.
7. The compound of claim 1 , wherein R is a stable linear chain three to five atoms in length having bonds selected from alkyl and ether linkages.
8. The compound of claim 1 , wherein R is —(CH 2 ) n —, where n is 3 to 5.
9. The compound of claim 1 , wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 5 to about 30.
10. The compound of claim 9 , wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 7 to about 15.
11. The compound of claim 9 , wherein the lipid L is a saturated or monounsaturated hydrocarbon.
12. The compound of claim 1 , wherein the ratio of nucleosides to groups —OR— in the polynucleoside moiety o is 1:1 or greater.
13. The compound of claim 1 , wherein o contains a sequence motif of at least three consecutive guanosine (G) nucleosides directly linked by NPS linkages.
14. The compound of claim 1 , wherein o contains a sequence motif GG(W) 1-3 GG, where G is guanosine and W is a nucleoside, and the linkages within said motif are N3→P5′ thiophosphoramidate (NPS) linkages.
15. The compound of claim 1 , wherein the lipid L is selected from a linear hydrocarbon, a fatty acid, and a fatty acid derivative, and is attached to the 3′ or 5′ terminus of said oligonucleoside.
16. The compound of claim 15 , wherein the lipid L is a C12 to C24 linear hydrocarbon.
17. The compound of claim 15 , wherein the lipid L is a palmitic or oleic acid derivative and is attached to said terminus via a glycerol or aminoglycerol linker.
18. The compound of claim 1 , containing at least one linkage 3′-NH—P(O)(S − )—O—R—Y—P(O)(S − )-5′, where Y is NH or O, and R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino.
19. The compound of claim 18 , where R is —(CH 2 ) 3 —.
20. A compound in accordance with claim 19 , wherein said compound is GRN163L A/Link.
21. A pharmaceutical composition comprising a compound as recited in claim 1 and a pharmaceutically acceptable carrier.
22. A method of treating cancer in a patient, by inhibiting adhesion of metastases comprising administering to the patient an effective amount of a compound having a structure represented by o-(x-L) n , where
(a) o is a polynucleoside moiety comprising a sequence of nucleosides and linkage moieties, wherein
(i) at least 50% of said linkage moieties are selected from: 3′NH—P(O)(S − )-5′; 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′; and 3′-Y—R—O—P(O)(S − )-5′, and at least 75% of the internucleoside linkage moieties are selected from 3′-NH—P(O)(S − )-5′ and 3′-NH—P(O)(S − )—{OR} m —Y—P(O)(S − )-5′; where Y is NH or O; R is a stable linear chain two to six atoms in length having bonds selected from alkyl, alkenyl, ether, thioether, and amino; and m is 1 to 3; and
(ii) said sequence includes at least one motif selected from GGG, GGWGG, and GGWWGG, containing residues selected from G and W, where G is guanosine and W is a nucleoside or the moiety —O—R—, where R is as defined above, and the inter-residue linkages within said motif are N3′→P5′ thiophosphoramidate (3′ NH—P(O)(S − )-5′) or phosphorothioate (3′-O—P(O)(S − )-5′) linkages;
(b) x is an optional linker group,
(c) L is a lipid moiety comprising a linear hydrocarbon moiety at least 12 carbon atoms in length, and
(d) n is 1 or 2;
wherein the compound o-(x-L) n is not a telomerase inhibitor,
wherein, subsequent to the administering step, treatment is effected.
23. The method of claim 22 , wherein said administering accompanies tumor biopsy or tumor-reductive surgery.