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Compound containing a labile disulfide bondRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 3 Or 4 Peptide Repeating Units In Known Peptide ChainCompound containing a labile disulfide bond description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191281, Compound containing a labile disulfide bond. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of Application Ser. No. 09/779,791, filed Feb. 8, 2001, pending, which is a continuation-in-part of Application Ser. No. 09/312,351 filed on May 14, 1999, pending, which claims the benefit of U.S. Provisional Application No. 60/085,764, filed on May 16, 1998. application Ser. No. 09/779,791 is incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Bifunctional molecules, commonly referred to as crosslinkers, are used to connect two molecules together. Bifunctional molecules can contain homo or heterobifunctionality. The disulfide linkage (RSSR') may be used within bifunctional molecules. The reversibility of disulfide bond formation makes them useful tools for the transient attachment of two molecules. Disulfides have been used to attach a bioactive compound and another compound (Thorpe, P. E. J. Natl. Cancer Inst. 1987, 79, 1101). The disulfide bond is reduced thereby releasing the bioactive compound. Disulfide bonds may also be used in the formation of polymers (Kishore, K., Ganesh, K. in Advances in Polymer Science, Vol. 21, Saegusa, T. Ed., 1993). [0003] There are many commercially available reagents for the linkage of two molecules by a disulfide bond. Additionally there are bifunctional reagents that have a disulfide bond present. Typically, these reagents are based on 3-mercaptopropionic acid, i.e. dithiobispropionate. However, the rate at which these bonds are broken under physiological conditions is slow. For example, the half life of a disulfide derived from dithiobispropionimidate, an analog of 3-mercaptopropionic acid, is 27 hours in vivo (Arpicco, S., Dosio, F., Brusa, P., Crosasso, P., Cattel, L. Bioconjugate Chem. 1997, 8, 327.). A stable disulfide bond is often desirable, for example when purification of linked molecules or long circulation in vivo is needed. For this reason, attempts have been made to make the disulfide less susceptible to cleavage. [0004] It has been demonstrated that both stability, measured as reduction potential, and rate, measured as rate constants, of disulfide reduction are both related to the acidity of the thiols which constitute the disulfide. Additional factors that may affect the rate of reduction are steric interactions, and intramolecular disulfide cleavage. Looking at the difference in the rates for the reactions RSH+R'SSR'.fwdarw.RSSR'+R'SH and RSH+R''SSR''.fwdarw.RSSR''+R''SH, it has been demonstrated that log k''/k'=.beta.(pK.sub.a.sup.R'-pK.sub.a.sup.R''), where k' and k'' are the rate constant for the reactions with R'SSR' and R''SSR'' respectively, pK.sub.a.sup.R' and pK.sub.a.sup.R'' are the acidities of the thiol groups R'SH and R''SH, and .beta. is a constant determined empirically to be 0.72. From this equation, one would predict that the reduction of a disulfide composed from relatively acidic thiols would be reduced more quickly than one composed of less acidic thiols. In support of this observation, it has been demonstrated that the disulfides cystine (pK.sub.a 8.3) and cystamine (pK.sub.a 8.2) are reduced 3-15 times faster than oxidized glutathione (pK.sub.a 8.9) (Bulaj, G., Kortemme, T., Goldenberg, D. P. Biochemistry 1998, 37, 8965). [0005] It has been demonstrated that both stability (thermodynamics), measured as reduction potential (Keire D. A. J. Org. Chem. 1992, 57, 123), and rate (kinetics), measured as rate constants, of disulfide reduction are both related to the acidity of the thiols which constitute the disulfide (Szajewski, R. P., Whitesides, G. M. J. Am. Chem. Soc. 1980, 102, 2011).The increase in acidity of a thiol is dependent upon one or more of the following structural factors: the presence of electron withdrawing groups which stabilize the thiolate through sigma and pi bonds (inductive effect), the presence of electron withdrawing groups that stabilize the thiolate through space or solvent (field effects), pi bonds which allow the negative charge to be placed on other atoms (resonance stabilization), and hydrogen bond donating groups within the molecule that can interact internally with the thiolate. For example, cysteine has an amino group two atoms from the thiol, which is more electron withdrawing than the amide nitrogen that is two atoms from the thiol in glutathione. As a consequence of this difference in electron withdrawing groups, the thiol of cysteine is 0.6 pK units more acidic than glutathione, and as mentioned previously, cystine is reduced 3-15 times faster than oxidized glutathione. Another example of a relatively acidic thiol is 5-thio-2-nitrobenzoic acid, pK.sub.a 5. Its acidity is due to resonance stabilization and inductive effects. Its disulfide is rapidly reduced by all standard alkyl thiols and its colored thiolate makes it a convenient assay for thiol concentration. SUMMARY OF THE INVENTION [0006] Described in a preferred embodiment is a process for the delivery of a compound to a cell, comprising associating a compound, containing a disulfide bond that can be cleaved under physiological conditions, with a polymer, then delivering the polymer to the cell. The polymer may comprise a first polymer and a second polymer. The first polymer and the second polymer may comprise nucleic acids, proteins, genes, antisense polymers, DNA/RNA hybrids, or synthetic polymers. [0007] In another preferred embodiment, a biologically active compound is associated with a disulfide-containing compound, comprising: the disulfide-containing compound having a labile disulfide bond that is selected from the group consisting of (a) a disulfide bond that is cleaved more rapidly than oxidized glutathione and (b) a disulfide bond constructed from thiols in which one of the constituent thiols has a lower pKa than glutathione and (c) a disulfide bond that is activated by intramolecular attack from a free thiol. [0008] In another preferred embodiment, a compound is provided for inserting into an organism, comprising: the compound having a disulfide bond that is labile under physiologic conditions selected from the group consisting of (a) a disulfide bond that is cleaved more rapidly than oxidized glutathione and (b) a disulfide bond constructed from thiols in which one of the constituent thiols has a lower pKa than glutathione and (c) a disulfide bond that is activated by intramolecular attack from a free thiol. [0009] In another preferred embodiment, a process is provided for forming a compound having a labile disulfide bond for use with an organism, comprising: forming the compound having a disulfide bond selected from the group consisting of (i) a disulfide bond that is cleaved more rapidly than oxidized glutathione, and (ii) a disulfide bond constructed from thiols in which one of the constituent thiols has a lower pKa than glutathione, and (iii) a disulfide bond that is activated by intramolecular attack from a free thiol; inserting the compound into the organism. [0010] In another preferred embodiment, a process is described for compacting a nucleic acid for delivery to a cell, comprising associating a polymer containing a disulfide bond with a nucleic acid and delivering the nucleic acid to the cell. [0011] In another preferred embodiment, a process is described for compacting a nucleic acid for delivery to a cell comprising associating a polymer with the nucleic acid, then associating a compound containing a disulfide bond that can be cleaved under physiological conditions with the nucleic acid polymer complex, then delivering the complex to a cell. [0012] In another preferred embodiment, a process is described for compacting a nucleic acid for delivery to a cell, comprising associating a polymer containing a disulfide bond with a nucleic acid, then associating another polymer with the disulfide containing polymer--nucleic acid complex, then delivering the complex to the cell. [0013] In another preferred embodiment, a process is described for compacting a nucleic acid for delivery to a cell comprising associating a polymer with the nucleic acid, then associating a compound containing a disulfide bond that can be cleaved under physiological conditions with the nucleic acid polymer complex, then associating another polymer with the complex, then delivering the complex to a cell. [0014] In another preferred embodiment, a compound is described which contains a disulfide bond that can be cleaved under physiological conditions and possesses heterobifunctional or homobifunctional groups. Such a compound can be described as a disulfide containing bifunctional molecule. A.sub.1-S--S-A.sub.2 [0015] More particularly, a compound that contains an aliphatic disulfide bond with one or more electronegative (electron withdrawing groups) substituted alpha or beta to one or both of the sulfur atoms. These groups serve to lower the pK.sub.a of the constituent thiols. [0016] Where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8--at least one of which is an electronegative atom or functionality such as OH, OR (an ether), NH.sub.2, (also secondary, tertiary, and quaternary amines), SO.sub.3.sup.-, COOH, COOR (an ester), CONH.sub.2, CONR.sub.2 (substituted amide), a halogen (F, Cl, Br, I), NO.sub.2. L is defined as a linker or spacer group that provides a connection between the disulfide and the reactive heterobifunctional or homobifunctional groups, A.sub.1 and A.sub.2. L may or may not be present and may be chosen from a group that includes alkanes, alkenes, alkynes, esters, ethers, glycerol, amide, urea, saccharides, polysaccharides, heteroatoms such as oxygen, sulfur, or nitrogen. The spacer may be charge positive, charge negative, charge neutral, or zwitterionic. A.sub.1 and A.sub.2 are reactive groups they may be identical as in a homobifunctional bifunctional molecule, or different as in a heterobifunctional bifunctional molecule. In a preferred embodiment, the disulfide compounds contain reactive groups that can undergo acylation or alkylation reactions. Such reactive groups include (but not limited to) isothiocyanate, isocyanate, acyl azide, acid halide, O-acyl urea, N-hydroxysuccinimide esters, succinimide esters, amide, urea, sulfonyl chloride, aldehyde, ketone, ether, epoxide, carbonate, alkyl halide, imidoester, carboxylate, alkylphosphate, arylhalides (e.g. difluoro-dinitrobenzene) or anhydrides. [0017] If functional group A1,A2 is an amine then A1,A2 can react with (but not restricted to) an activated carboxylic acid, isothiocyanate, isocyanate, acyl azide, alkyl halide, acid halide, N-hydroxysuccinimide ester, sulfonyl chloride, aldehyde, ketone, epoxide, carbonate, imidoester, amide, carboxylate, or alkylphosphate, arylhalides (difluoro-dinitrobenzene) or anhydrides. In other terms when function A1,A2 is an amine, then an acylating or alkylating agent can react with the amine. [0018] If functional group A1,A2 is a sulfhydryl then A1,A2 can react with (but not restricted to) a haloacetyl derivative, activated carboxylic acid, maleimide, aziridine derivative, acryloyl derivative, fluorobenzene derivatives, or disulfide derivative (such as a pyridyl disulfide or 5-thio-2-nitrobenzoic acid{TNB} derivatives). [0019] If functional group A1,A2 is carboxylate then A1,A2 can react with (but not restricted to) a diazoacetate, alcohol, thiol or an amine once the acid has been activated. [0020] If functional group A1,A2 is an hydroxyl then A1,A2 can react with (but not restricted to) an activated carboxylic acid, epoxide, oxirane, or an amine in which carbonyldiimidazole is used. [0021] If functional group A1,A2 is an aldehyde or ketone then A1,A2 can react with (but not restricted to) an hydrazine, hydrazide derivative, amine (to form a Schiff Base that may or may not be subsequently reduced by reducing agents such as NaCNBH.sub.3), or a diol to form an acetal or ketal. Continue reading about Compound containing a labile disulfide bond... 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