Paclitaxel Prodrugs: Toward Smarter Delivery of Anticancer Agents

Abstract

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ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

“…Three examples are shown here, each of which has a different story to tell. Besides the objectives discussed above, it is also useful to classify prodrugs using chemical and biochemical arguments [38 -45] [56]. The drug does have affinity for the benzodiazepine receptor [22b], but it appears incapable of crossing the blood -brain barrier and is rapidly metabolized to its two active metabolites [24].…”

“…Numerous carrier-linked prodrugs have been prepared from drugs containing an adequate functional group. Our second example is a bioprecursor (i.e., devoid of a promoiety) activated by intramolecular migration, namely isotaxel (5.33), a prodrug of the potent antitumor agent paclitaxel (5.34) [56] [60]. 5.18 -5.20 for three types of functional groups which are frequent sites of derivatization to form prodrugs [14] [38] [41].…”

Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2′-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes

“…The poor aqueous solubility of paclitaxel is also a problem for intravenous administration. To overcome these drawbacks, a number of investigators have developed paclitaxel prodrugs and conjugates based on the chemical modification of the hydroxyl groups at position 7 of the baccatin core and/or position 2′ of the paclitaxel side chain 2–4 . In our previous studies, 2′‐ethylcarbonate‐linked paclitaxel (TAX‐2′‐Et; Figure 1) showed a low sensitivity to hydrolytic enzymes in human serum, and circumvented P‐glycoprotein (P‐gp)‐mediated efflux of paclitaxel in paclitaxel‐resistant cells, demonstrating one of the most important factors of gene‐directed enzyme prodrug therapy (GDEPT) strategies that allow the tumour cell‐specific cytotoxicity of paclitaxel 5,6 …”

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

“…[5,[18][19][20][21][22][23] In the past three decades, this tracelessa nd quantitative Oto-N acyl shift has attracted considerable attentiona nd been used in various areas. [24][25][26] In addition, similart ransformations requiring an intermediate of as ix-membered ring or larger have also been broadly investigated. To be consistentw ithn omenclature throughout this text,w et erm the meta-stable chemicals tructure unit possessing both ester and amine (primary or secondary) groups as "isoacyl structural motif" or "iso-acyl motif"( Scheme1).…”