Compounds having anti-adhesive effects on cancer cells
AssigneesGeron Corporation, Board of Regents, The University of Texas System
InventorsSergei M. Gryaznov, Jerry W. Shay, Woodring Wright
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Abstract
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.
Claims23
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.
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.
Dependencies are inferred from the claim text.