184874-53-1Relevant academic research and scientific papers
Duocarmycin-based prodrugs for cancer prodrug monotherapy
Tietze, Lutz F.,Schuster, Heiko J.,Schmuck, Kianga,Schuberth, Ingrid,Alves, Frauke
, p. 6312 - 6318 (2008/12/20)
The synthesis and biological evaluation of novel prodrugs based on the cytotoxic antibiotic duocarmycin SA (1) for a selective treatment of cancer using a prodrug monotherapy (PMT) are described. Transformation of the phenol 8 with the glucuronic acid benzyl ester trichloroacetimidate 9b followed by reaction with DMAI·HCl (10) gives the glucuronide 11b, which is deprotected to afford the desired prodrug 4a containing a glucuronic acid moiety. In addition, the prodrug 4b with a glucuronic methyl ester unit is prepared. The cytotoxicity of the glucuronides is determined using a HTCFA-assay with IC50 values of 610 nM for 4a and 3300 nM for 4b. In the presence of β-glucuronidase, 4a expresses an IC50 value of 0.9 nM and 4b of 2.1 nM resulting in QIC50 values of about 700 for 4a and 1600 for 4b.
Synthesis and enzymatic evaluation of substrates and inhibitors of β-glucuronidases
Hoos,Huixin,Vasella,Weiss
, p. 1757 - 1784 (2007/10/03)
The phosphono and the tetrazolyl analogues 4 and 5 of 4-methylumbelliferyl β-D-glucuronide (= (4-methyl-2-oxo-2H-1-benzopyran-7-yl β-D-glucopyranosid)uronic acid; 6) were synthesized and evaluated as substrates of β-glucuronidases. Similarly, the phenylcarbamate 7 and its phosphono analogue 8 were prepared and evaluated as inhibitors. To examine the diastereoselectivity of the phosphorylation, we also synthesized the protected L-ido-, D-gluco-, and D-galacto-configurated phospha-glycopyranuronates 12, 13, 21, 22, 34 and 35. Two strategies were followed. In the first one, the glucuronic acid 19 was decarboxylated to 11 and further transformed, via 20, into the trichloroacetimidate 10. Phosphorylation of 10 with (MeO)3P yielded the diastereoisomers 12 and 13, the diastereoselectivity depending on the solvent. In MeCN, 12 and 13 were obtained in a ratio of 1:1, while in non-participating solvents the L-ido 12 was by far the major diastereoisomer. The acetate 11 was inert to (MeO)3P, but reacted with (PhO)3P to the anomeric mixture 21/22, in keeping with a stabilizing 1,3-interaction in the intermediate phosphonium salt. Similarly, the phospha-galacturonates 34 and 35 were prepared from the galactoside 23 via the enol ether 26, the lactone 27, and the acetates 28/29 that were also transformed into the trichloroacetimidate 33. In the second, higher-yielding strategy, phosphorylation of the pentodialdehyde 39 to 40/41 was followed by hydrolysis and acetylation to the phospha-glucuronates 43/44. Transesterification to 45/46, selective deacetylation to 48/49, and formation of the trichloroacetimidates 50/51 were followed by glycosidation and deprotection to 4. The tetrazole 5 was prepared from the lactones 54/55 via the N-benzylamides 57/58 that were treated with TfN3 to give the N-benzyltetrazoles 59/60. These were transformed into the trichloroacetimidates 63/64, glycosylated to 65, and deprotected. The O-carbamoylhydroximo-lactone 7 derived from the glucuronate 67/68, and the phosphonate analogue 8 were prepared by established methods. The phosphonate 4 is slowly hydrolyzed by the E. coli β-glucuronidase, but neither 4 nor the tetrazole 5 are affected by the bovine liver β-glucuronidase. The phenylcarbamate 7 of D-glucarhydroximo-1,5-lactone, but not its phosphonate analogue 8, is an inhibitor (K(I) = 8 μM) of the E. coli β-glucuronidase. The bovine liver β-glucuronidase is inhibited strongly by 7 (IC50 = 0.2 μM) and weakly by 8 (IC50 = 2 mM).
