Probing the Cysteine-34 Position of Endogenous Serum Albumin with Thiol-Binding Doxorubicin Derivatives. Improved Efficacy of an Acid-Sensitive Doxorubicin Derivative with Specific Albumin-Binding Properties Compared to That of the Parent Compound

Abstract

We have recently proposed a macromolecular prodrug strategy for improved cancer chemotherapy based on two features (Kratz, F.; et al. J. Med. Chem 2000, 43, 1253-1256.): (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration and (b) release of the albumin-bound drug in the acidic environment at the tumor site due to the incorporation of an acid-sensitive bond between the drug and the carrier. To investigate this therapeutic strategy in greater depth, four (maleinimidoalkanoyl)hydrazone derivatives of doxorubicin were synthesized differing in the length of the aliphatic spacer (1, -(CH(2))(2)-; 2, -(CH(2))(3)-; 3, -(CH(2))(5)-; 4, -(CH(2))(7)-). The albumin-binding doxorubicin prodrugs, especially the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (3), are rapidly and selectively bound to the cysteine-34 position of endogenous albumin. 3 was distinctly superior to the parent compound doxorubicin in three animal tumor models (RENCA, MDA-MB 435, and MCF-7) with respect to antitumor efficacy and toxicity.

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

“…The growth media within individual wells was then manually removed by pipette and the adherent mammary adenocarcinoma SKBr-3 monolayers serially rinsed (n = 3) with PBS followed by stabilization on the plastic surface of microtiter plates with paraformaldehyde (4% in PBS, 15 minutes). Stabilized mammary adenocarcinoma SKBr-3 monolayers were then incubated with covalent epirubicin-(C 3 Contents within individual 96-well microtiter plate wells were manually removed by pipette at 72 hours and then the mammary adenocarcinoma SKBr-3 monolayers were serially rinsed (n = 3) with PBS followed by incubation with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT formulated at 5 mg/mL in RPMI-1640 growth media devoid of pH indicator or bovine fetal calf serum). During a 3-hour incubation period at 37°C under a gas atmosphere of air (95%) and carbon dioxide (5% CO 2 ) mammary adenocarcinoma SKBr-3 populations were allowed to biochemically convert intracellular MTT to navy-blue formazone crystals by endogenous mitochondrial succinate dehydrogenase.…”

Isomerization/recyclization of some 5-ethoxycarbonyl-pyrimidines

“…To a solution of 1 g (7.2 mmol) of 2-hydrazino-4,6-dimethylpyrimidine [17] in 40 mL of ethanol, was added 1.1 g (7.2 mmol) of 2-hydroxy-4-methyl-5-acetylpyrimidine (3) and 3-4 mL of hydrochloric acid, and the mixture was heated under reflux for 10-12 h. On completion the mixture was cooled and the precipitate of the unreacted acetylpyrimidine was filtered off. After removal of the solvent from the alcoholic solution the solid residue was recrystallized from the mixture benzene-acetone (1:1).…”

“…Taking into account the interesting biological behavior of hydrazones and their metal complexes as antitumor [17][18][19], antiviral [20] and antibacterial and antifungal compounds [21,22], keto-pyrimidines -5-acetyluracil (2a) and 2-hydroxy-4-methyl-5-acetylpyrimidine (3) were transformed to their hydrazones (7)(8)(9)(10)(11)(12) by reactions with substituted hydrazines and isonicotinic hydrazide.…”

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

“…[4][5][6][7][8] We have recently developed an albumin-binding prodrug of doxorubicin that is cleaved by PSA, i.e., EMC-Arg-Arg-Ser-SerTyr-Tyr-Ser-Gly-DOXO (EMC 5 6-maleimidocaproic acid; DOXO 5 doxorubicin. 9 Our drug targeting strategy is based on 2 features [10][11][12] : (i) in situ binding of a thiol-binding prodrug to the cysteine-34 position of circulating albumin after intravenous administration with subsequent accumulation of the drug albumin conjugate in the tumor because of passive targeting; (ii) release of the albumin-bound drug at the tumor site because of the incorporation of a cleavable bond between the drug and the carrier.…”