High specificity anticancer drug design process

Abstract

A process for producing new anticancer drugs such that the drugs can be administered in a nontoxic, proto-drug form and, subsequent to a time delay which allows for differential concentration in the targer cancer or invasive tissues or cells, the non-toxic drug is then modified by an activation drug to selectively provide toxic levels of a pharmacologically active agent to the target issue.

1 . An assemblage comprising a substantially biologically inert proto-drug and a substantially biologically inert activation drug, whereby the proto-drug comprises a differentially selective moiety, a toxic moiety and a cap moiety and whereas the moieties of the proto-drug are linked together in such a manner as to make the proto-drug itself substantially inert.  
     
     
         2 . A process for the preparation of a substantially biologically inert proto-drug whereby the process comprises: 
 (a) selection of a differentially concentrating moiety by a method chosen from the group consisting of differential HPLC, differential chromatography, and in vivo differential rate analysis;    (b) selection of a toxic moiety by a method chosen from the group consisting of in vitro testing, in vivo testing and evaluation of published lists of toxic moieties;    (c) selection of a cap moiety by a method chosen from the group consisting of in vitro testing, in vivo testing and evaluation of published lists of reagents with the toxic moiety; and    (d) linking the differentially concentrating moiety, the toxic moiety, and the cap moiety in such a manner as to make the proto-drug itself substantially biologically inert.    
     
     
         3 . A process for the preparation of an assemblage, whereby the process comprises: 
 (a) selection of a differentially concentrating moiety by a method chosen from the group consisting of differential HPLC, differential chromatography, and in vivo differential rate analysis;    (b) selection of a toxic moiety by a method chosen from the group consisting of in vitro testing, in vivo testing and evaluation of published lists of toxic moieties;    (c) selection of a cap moiety by a method chosen from the group consisting of in vitro testing, in vivo testing and evaluation of published lists of reagents with the toxic moiety;    (d) selection of an activation drug by a method chosen from the group consisting of in vitro testing, in vivo testing and evaluation of published lists of reagents with the cap moiety; and    (e) linking the differentially concentrating moiety, the toxic moiety, and the cap moiety in such a manner as to make the proto-drug itself substantially biologically inert.    
     
     
         4 . A method of treating neoplasms in a mammal, such method comprising: 
 (a) administering to a mammal in need of such treatment an effective amount of a proto-drug, such proto-drug comprising a differentially concentrating moiety, a toxic moiety and a cap moiety;    (b) waiting for a time delay period; and    (c) administering to the mammal an activating amount of an activation drug whereby the activation drug converts the proto-drug in vivo to a pharmacologically active compound.    
     
     
         5 . A method of converting a substantially biologically inert compound to a pharmacologically active agent, such method comprising: 
 (a) administering to a mammal a proto-drug, such proto-drug comprising a differentially concentrating moiety, a toxic moiety, and a cap moiety whereby the moieties are linked together in such a fashion as to create a biologically inert compound;    (b) waiting for a time delay period; and    (c) administering to the mammal an activation amount of an activation drug whereby the activation drug converts the proto-drug to a pharmacologically active agent.    
     
     
         6 . A method of selectively delivering a cytotoxic compound to tumor tissue, such method comprising administering to a mammal a proto-drug comprising a differentially concentrating moiety, a toxic moiety and a cap moiety, whereby the proto-drug delivers a cytotoxic compound to the tumor tissue in such a manner as to prevent significant damage to normal tissues by maintaining the cap moiety on the proto-drug until the proto-drug differentially concentrates in the tumor tissue during a time delay, and after such time delay the proto-drug produces a cytotoxic compound upon administration of an activation drug.  
     
     
         7 . A pharmaceutical preparation comprising: 
 (a) an effective amount of a proto-drug together with a pharmaceutically acceptable excipient; and    (b) an activating amount of an activation drug together with a pharmaceutically acceptable excipient whereby the proto-drug and the activation drug are packaged for individual administration.    
     
     
         8 - 24 . (Cancelled)  
     
     
         25 . A method of determining a time delay period between administration of a proto-drug and an activation drug which comprises determining time T in the equation 
         R=E   A   /E   B =( b   B   /b   A ) exp[( b   B   −b   A ) T]   whereby:    R is the ratio of the diffusion constants of cell types A and B;    E A  is the exposure of cell type A to the proto-drug;    E B  is the exposure of cell type B to the proto-drug;    b A  is the elimination constant of cell type A; and    b B  is the elimination constant of cell type B.    
     
     
         26 . The method of  claim 25  whereby the time delay period is evaluated by in vivo procedures.  
     
     
         27 . A proto-drug comprising: 
 (a) a thioxanthone moiety that acts as a differentially concentrating moiety;    (b) a mechlorethamine or podophyllotoxin moiety that acts as a toxic moiety; and    (c) a silane moiety that acts as a cap moiety whereby the thioxanthone, mechlorethamine or podophyllotoxin, and silane moieties are linked to form a substantially biologically inert compound.    
     
     
         28 - 33 . (Cancelled).  
     
     
         34 . An assemblage comprising a substantially biologically inert proto-drug and a substantially biologically inert activation drug, whereby the proto-drug comprises 
 (a) a thioxanthone moiety that acts as a differentially concentrating moiety;    (b) a mechlorethamine or podophyllotoxin moiety that acts as a toxic moiety;    (c) a silane moiety that acts as a cap moiety; and    the activation drug is a fluoride salt.    
     
     
         35 . The assemblage of  claim 34  whereby the fluoride salt is sodium fluoride.