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 method of inhibiting cell adhesion, comprising contacting said cells with 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′, 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 and GG(W) 1-3 GG, containing residues G and/or 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, and (d) n is 1 or 2; wherein the compound is not a telomerase inhibitor.
2. The method of claim 1 , wherein said cells are cancer cells.
3. The method of claim 1 , wherein Y is NH.
4. The method of claim 1 , wherein m is 1.
5. The method of claim 1 , wherein said inter-residue linkages are 3′-NH—P(O)(S − )-5′ (NPS) linkages.
6. The method of claim 1 , wherein at least 50% of internucleoside linkages are 3′-NH—P(O)(S − )-5′ (NPS) linkages.
7. The method of claim 1 , if wherein R is a stable linear chain three to five atoms in length having bonds selected from alkyl and ether linkages.
8. The method of claim 1 , wherein R is —(CH 2 ) n —, where n is 3 to 5.
9. The method of claim 1 , wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 5 to about 30.
10. The method of claim 1 , wherein the sum of nucleosides and groups —OR— in the polynucleoside moiety o is from 7 to about 15.
11. The method of claim 1 , wherein o contains a sequence motif of at least three consecutive guanosine (G) nucleosides directly linked by NPS linkages.
12. The method 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.
13. The method 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.
14. The method of claim 13 , wherein the lipid L is a C12 to C24 linear hydrocarbon.
15. The method of claim 14 , wherein the lipid L is a palmitic or oleic acid derivative and is attached to said terminus via a glycerol or aminoglycerol linker.