Doxorubicin, prodrugs

S. R. Khan, S. R. Denmeade, In vivo Activity of a PSA-Activated Doxorubicin Prodrug against PSA-Producing Human Prostate Cancer Xenografts , Prostate 2000, 45, 80-83. 

Seymour, L. W., Ulbrich, K., Steyger, P. S., et al. Tumor tropism and anticancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma. Br. J. Cancer 70 636-641, 1994. 

The half-lives of cathepsin B cleavage of doxorubicin prodrug 41 and mitomycin C prodrug 43 were much shorter than those of paclitaxel prodrugs 40 and 42, indicating steric hindrance by the paclitaxel part of the prodrug.4... 

Zhou L, Cheng R, Tao H, Ma S, Guo W, Meng F. Endosomal pH-activatable poly(ethylene oxide)-graft-doxorubicin prodrugs synthesis, drug release, and biodistribution in tumor-bearing mice. Biomacromolecules 2011 12 1460-7. 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

Interestingly, a closely related prodrug of doxorubicin that has the same spacer (i.e., 6.33) was found to be a good substrate for plasmin while being stable in buffer and blood serum [55], A marked selectivity was seen against a plasmin-generating MCF-7 breast cancer cell line. 

G. M. Dubowchik, R. A. Firestone, Cathepsin B-Sensitive Dipeptide Prodrugs. 1. A Model Study of Structural Requirements for Efficient Release of Doxorubicin , Bioorg. Med. Chem. Lett. 1998, 8, 3341-3346. 

The so-called self-immolative prodrugs are other relevant and intriguing examples as candidates for ADEPT (Fig. 8.17). Here, the primary bioactivation product is not the active agent, but an intermediate that breaks down spontaneously to liberate this active agent. Various cytotoxic drugs that bear an amino group were investigated, i. e., 4-[bis(2-chloroethyl)amino]aniline, actinomycin D, doxorubicin, and mitomycin C [206]. These were trans-... 

Komatsu K (2005) The Mechanochemical Solid-State Reaction of Fullerenes. 254 185-206 Kratz F (2008) Acid-Sensitive Prodrugs of Doxorubicin. 283 73-97 Kremsner JM, Stadler A, Kappe CO (2006) The Scale-Up of Microwave-Assisted Organic Synthesis. 266 233-278... 

Cogan, P. S., Fowler, C. R.,Post, G. C., and Koch, T. H. Doxsaliform A novel A-Mannich base prodrug of a doxorubicin formaldehyde conjugate (letter). Drug Des. Discov. 1 247-255, 2004. 

Several ADEPT systems that are beyond the scope of this chapter have been studied extensively and are the subject of many reviews.15,92-93 One of the most widely cited ADEPT systems employs a glucouronidase (GUS)-monoclonal antibody conjugate that activates a doxorubicin-glu-curonide prodrug. Studies have shown that there is a substantial therapeutic benefit, a higher level of drug in tumor tissue when compared... 

Denmeade SR, Nagy A, Gao J, Lilja H, Schally AV, Isaacs JT. Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res 1998 58 2537-2540. 

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin. and the metalchelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent. 

A prodrug with a direct linkage of a peptide to doxorubicin)... 

Prodrugs with one spacer between a peptide and doxorubicin or its derivatives)... 

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