Cancer Chemotherapy: A Paclitaxel Prodrug for ADEPT (Antibody‐Directed Enzyme Prodrug Therapy)

Abstract

A glucuronide‐based prodrug of paclitaxel (taxol®) has been synthesized for use in antibody‐directed enzyme prodrug therapy (ADEPT). This three‐component prodrug was obtained by coupling a glucuronyl derivative of N‐methylamino 4‐nitrophenol (10) to the 2′‐hydroxy group of the side‐chain of paclitaxel through an aromatic carbamate. Once deprotected, prodrug 2 was shown to be relatively stable in human serum, and to be significantly less cytotoxic (IC50 = 65 μM and 90 nM, respectively) than the parent drug. As expected, compound 2 efficiently releases taxol in the presence of β‐glucuronidase.

Delivery of Nitric Oxide Released from .BETA.-Gal-NONOate Activation by .BETA.-Galactosidase and Its Activity against Escherichia coli

“…NO production is a necessary component of non-specific defense mechanism against several pathogens including bacteria, viruses, fungi and parasites. 13,14) However, NO has an extremely short half-life, so it is difficult to utilize this active small molecule in therapy and research. Thus, a variety of NO donor prodrugs have been developed, for example, sodium nitroprusside (SNP), hydroxyurea and synthetic hydroxyurea derivatives, NONOates.…”

Recent Developments in Taxane Drug Delivery

“…Bosslet et al mor-targeting segment, the Fab part of the anti-carcinoembryonic antigen MAb, BW 431, and a linker-cleaving moiety, humanglucuronidase [96]. Subsequently, a number of PTX-glucuronic acid conjugates such as the one shown by structure 18 were reported as candidates for ADEPT, which also had a somewhat better water solubility than the parent drug [97,98].…”

“…In cytotoxicity assays with LoVo cells, conjugate 18 showed an IC 50 of 65 μM, which was about 700-fold less active than PTX. However, the IC 50 increased to 100 nM in the presence of ß-glucoronidase (ß-Gase) [98]. Schimidt et al later reported the synthesis of PTX-and DTXglucoronic acid conjugates (19, 20, and 21), respectively) with elongated linkers to reduce the steric hindrance effects of the bulky drug nuclei [97,99].…”

“…Schimidt et al later reported the synthesis of PTX-and DTXglucoronic acid conjugates (19, 20, and 21), respectively) with elongated linkers to reduce the steric hindrance effects of the bulky drug nuclei [97,99]. These researchers showed that 19 had a faster rate of decomposition in the presence of -Gase than in either straight phosphate buffer or phosphate buffer in the presence of human serum (HS) [98]. No information was provided on the t 1/2 of this conjugate in the presence of both HS and the -Gase.…”

Taxol: Synthesis, Bioactive Conformations, and Structure-Activity Relationships in Its Analogs

“…However, some 7-deoxy-10-deacetyltaxol analogs 128 [R = R' = Me(CH 2 ) 4 CO, R = R' = Me(CH 2 ) 6 CO, R = R' = PhCH=CHCO] are noncyto-337 toxic; presumably, their hydrolysis is more difficult [207]. The design of prodrugs via replacement of the 2'-hydroxy group in taxol was the subject of extensive studies [157,169,183,207,232,236,[239][240][241][242].…”