220913-32-6Relevant articles and documents
Semisynthesis of DB-67 and other silatecans from camptothecin by thiol-promoted addition of silyl radicals
Du, Wu,Kaskar, Bashir,Blumbergs, Peter,Subramanian,Curran, Dennis P.
, p. 451 - 458 (2003)
Thiol- or acid-promoted additions of silyl radicals to camptothecin are reported. At 105°C, mixtures of 7-silyl (favored) and 12-silyl camptothecins are formed alongside substantial amounts of recovered camptothecin. At 160°C, 12-silyl isomers are formed
Stable supersaturated aqueous solutions of silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin via chemical conversion in the presence of a chemically modified β-cyclodextrin
Xiang, Tian-Xiang,Anderson, Bradley D.
, p. 1215 - 1222 (2002)
Purpose. A method for obtaining clear supersaturated aqueous solutions for parenteral administration of the poorly soluble experimental anti-cancer drug silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) has been developed. Methods. Equilibrium solubilities of DB-67 were determined in various solvents and pH values, and in the presence of chemically modified water-soluble β-cyclodextrins. The stoichiometry and binding constants for complexes of the lactone form of DB-67 and its ring-opened carboxylate with sulfobutyl ether and 2-hydroxypropyl substituted β-cyclodextrins (SBE-CD and HP-CD) were obtained by solubility and circular dichroism spectroscopy, respectively. Kinetics for the reversible ring-opening of DB-67 in aqueous solution and for lactone precipitation were determined by HPLC with UV detection. Results. Solubilities of DB-67 lactone in various injectable solvent systems were found to be at least one order of magnitude below the target concentration (2 mg/ml). DB-67 forms inclusion complexes with SBE-CD and HP-CD but the solubilization attainable is substantially less than the target concentration. Slow addition of DB-67/DMSO into 22.2% (w/v) SBE-CD failed to yield stable supersaturated solutions due to precipitation. Stable supersatured solutions were obtained, however, by mixing a concentrated alkaline aqueous solution of DB-67 carboxylate with an acidified 22.2% (w/v) SBE-CD solution. Ring-closure yielded supersaturated solutions that could be lyophilized and reconstituted to clear, stable, supersaturated solutions. Conclusions. The method developed provides an alternative to colloidal dispersions (e.g., liposomal suspensions, emulsions, etc.) for parenteral administration of lipophilic camptothecin analogs.
METHODS AND SYSTEMS FOR CAMPTOTHECIN ANALOG SYNTHESIS
-
, (2016/05/19)
Methods and systems for making camptothecin analogs and intermediates are provided. Aspects include safer and lower cost methodologies for making camptothecin analogs and intermediates from synthetic materials. In another aspect, the methods and systems c
Palladium-promoted cascade reactions of isonitriles and 6-iodo-N-propargylpyridones: synthesis of mappicines, camptothecins, and homocamptothecins.
Curran, Dennis P,Du
, p. 3215 - 3218 (2007/10/03)
Ambient-temperature reactions of electron-rich aryl isonitriles with substituted 6-iodo-N-propargylpyridones in the presence of silver carbonate and palladium acetate produce 11H-indolizino[1,2-b]quinolin-9-ones in good to excellent yield. Experimental ev
Synthesis of silyl camptothecins and silyl homocamptothecins
-
Example 4, (2008/06/13)
A method of synthesizing 7-silyl camptothecins and 7-silyl homocamptothecins includes the step of mixing a camptothecin or a homocamptothecin having hydrogen at the C7 position with a silyl radical generator and a silyl radical precursor under conditions to generate a silyl radical. SiR1R2R3wherein R1, R2and R3are independently a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, an aryl group, —(CH2)mR11or SiR12R13R14, wherein m is an integer within the range of 1 through 10 and R11is a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, F, Cl, a cyano group, —SRcor a nitro group, and wherein R12, R13and R14are independently the same or different an alkyl group or an aryl group.
The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity
Bom,Curran,Kruszewski,Zimmer,Strode,Kohlhagen,Du,Chavan,Fraley,Bingcang,Latus,Pommier,Burke
, p. 3970 - 3980 (2007/10/03)
We describe the rational design and synthesis of B- and A,B-ring-modified camptothecins. The key α-hydroxy-δ-lactone pharmacophore in 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67, 14) displays superior stability in human blood when compared with clinically relevant camptothecin analogues. In human blood 14 displayed a t( 1/2 ) of 130 rain and a percent lactone at equilibrium value of 30%. The tert-butyldimethylsilyl group renders the new agent 25-times more lipophilic than camptothecin, and 14 is readily incorporated, as its active lactone form, into cellular and liposomal bilayers. In addition, the dual 7-alkylsilyl and 10-hydroxy substitution in 14 enhances drug stability in the presence of human serum albumin. Thus, the net lipophilicity and the altered human serum albumin interactions together function to promote the enhanced blood stability. In vitro cytotoxicity assays using multiple different cell lines derived from eight distinct tumor types indicate that 14 is of comparable potency to camptothecin and 10-hydroxycamptothecin, as well as the FDA-approved camptothecin analogues topotecan and CPT-11. In addition, cell-free cleavage assays reveal that 14 is highly active and forms more stable top1 cleavage complexes than camptothecin or SN-38. The impressive blood stability and cytotoxicity profiles for 14 strongly suggest that it is an excellent candidate for additional in vivo pharmacological and efficacy studies.
