Carbonic anhydrase inhibitors: Synthesis of N-morpholylthiocarbonylsulfenylamino aromatic/heterocyclic sulfonamides and their interaction with isozymes I, II and IV

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 10, 2000, Pages 1117-1120

  Scozzafava, Andrea ^a   Supuran, Claudiu T ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CARBONATE DEHYDRATASE INHIBITOR; CARBONYL DERIVATIVE; ISOENZYME; N MMORPHOLYL-THIOCARBONYLSULFENYLAMINO; SULFONAMIDE; UNCLASSIFIED DRUG;

ARTICLE; CANCER INHIBITION; DRUG SYNTHESIS; ENZYME INHIBITION; ENZYME INHIBITOR INTERACTION; IN VITRO STUDY; TUMOR CELL LINE;

CARBONIC ANHYDRASE INHIBITORS; CARBONIC ANHYDRASES; CELL DIVISION; DRUG SCREENING ASSAYS, ANTITUMOR; HETEROCYCLIC COMPOUNDS; HUMANS; MORPHOLINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TUMOR CELLS, CULTURED;

EID: 0034658561     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00178-5     Document Type: Article

References (23)

1. Supuran, C. T.; Briganti, F.; Tilli, S.; Chegwidden, W. R.; Scozzafava, A. J. Med. Chem., in press.
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12. For example, by using sodium hypochlorite as oxidizing agent, the followed procedure was: an amount of 10 mMols sulfonamide 1-20 was treated with 100 mL of a solution containing 0.8 g (20 mMols) sodium hydroxide (KOH could also be used). After dissolution of the sulfonamide, into the magnetically stirred reaction mixture were slowly (1-2 h) and concomitantly dropped the following two aqueous solutions: (i) 50 mL of a solution containing 10 mMols of sodium/potassium N-morpholyldithiocarbamate 21; and (ii) 50 mL of NaClO solution, containing the stoichiometric amount (10 mMols) of oxidizing agent. The temperature was maintained in the range of 25-30 °C (generally cooling of the reaction mixture had to be done), with strong magnetic stirring, for 1-3 h (TLC control; the thiocarbamylsulfenamide and the thiuram 22 started to precipitate immediately after the addition of the oxidizing agent). A double-2.5-fold amount of initial sulfonamide could be used in the synthesis (for relatively inexpensive raw materials, such as 3-6, for example), case in which the yields in thiocarbamylsulfenamides were increased. In order to purify the obtained thiocarbamylsulfenamides, the obtained crude precipitate was filtered and treated with an excess (100-150 mL) of a 0.03-0.05 M NaOH (or KOH) and magnetically stirred for 30 min at 4 °C. The insoluble thiuram was filtered and the sodium/potassium salts of the thiocarbamylsulfenamides acidified with a 10% HCl solution (till pH 5.5), when the pure A(1-20) precipitated. They were then filtered, thoroughly washed with water and air dried. Yields were generally in the range of 25-40%, but for some derivatives they were much higher (around 70-75 % for A3, A5 and A6).
13. i was determined as described in ref 8. Enzyme concentrations were 3.0 nM for hCA II, 9 nM for hCA I and 28 nM for bCA IV.
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23. 50 is in fact the molarity of inhibitor at which PG=50%. The standard sulforhodamine B (SRB) protein assay has been used to estimate cell viability or growth (cf. Teicher, B. A. (Ed.). Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval; Humana Press Inc.: Totowa, NJ, 1997; pp 7-125).