The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs

Abstract

Anticancer drugs are presently guarantying more survivors as a result of more powerful drugs or combinations of drugs used in therapy. Thus, it has become more crucial to study and overcome the side effects of these therapies. Cardiotoxicity is one of the most relevant side effects on the long-term cancer survivors, because of its high social and economic impact. Drug metabolism can result in active metabolites or toxic metabolites that can lead to important side effects. The metabolites of anticancer drugs are possible culprits of cardiotoxicity; however, the cardiotoxicity of many of the metabolites in several drug classes was not yet suitably studied so far. On the other hand, the use of prodrugs that are bioactivated through metabolism can be a good alternative to obtain more cardio safe drugs. In this review, the methods to obtain and study metabolites are summarized and their application to the study of a group of anticancer drugs with acknowledged cardiotoxicity is highlighted. In this group of drugs, doxorubicin (DOX, 1), mitoxantrone (MTX, 2), cyclophosphamide (CTX, 3) and 5-fluorouracil (5-FU, 4) are included, as well as the tyrosine kinase inhibitors, such as imatinib (5), sunitinib (6) and sorafenib (7). Only with the synthesis and purification of considerable amounts of the metabolites can reliable studies be performed, either in vitro or in vivo that allow accurate conclusions regarding the cardiotoxicity of anticancer drug metabolites and then pharmacological prevention or treatment of the cardiac side effects can be done.

Metabolism Mimicry: An Electrosynthetic Method for the Selective Deethylation of Tertiary Benzamides

“…To probe the feasibility of developing an electrochemical Ndealkylation of tertiary amides, a model system of structural similarity to the insect repellent DEET was selected 1 a (Figure 2). Our original results with 1 a under potentiostatic conditions [7b] afforded in high conversion (95 %) the expected �methoxylated Shono product (2 a) with a trace amount of the enamide (5). More recently efficient methods to prepare Shonotype products have been reported under controlled current conditions.…”

“…It is a requirement of the FDA that all detectable metabolites of a new drug entity are prepared for rigorous toxicological studies which necessitates currently their de novo synthesis, which although is not insurmountable, can require tremendous intellectual and practical effort to achieve …”

“…[3] It is a requirement of the FDA [4] that all detectable metabolites of a new drug entity are prepared for rigorous toxicological studies which necessitates currently their de novo synthesis, which although is not insurmountable, can require tremendous intellectual and practical effort to achieve. [5] A commonly encountered metabolism pathway is the Ndealkylation of a drug molecule which occurs during phase I metabolism through an isoform of the heme-mediated cytochrome P450 enzyme (CYP450). [6] This transformation increases the polarity of the drug molecule and alongside subsequent phase II conjugation enables the drug to be eliminated from the body.…”

Pixantrone, a new anticancer drug with the same old cardiac problems? An in vitro study with differentiated and non-differentiated H9c2 cells

“…Anticancer drugs, however, lack total selectivity, which results in serious side effects (Hrynchak et al ., 2017; Reis-Mendes et al ., 2015). Cardiotoxicity is one of the most worrying side effect found in patients treated with anticancer drugs of several pharmacological groups, like anthracyclines [ e.g .…”

“…doxorubicin (DOX)] and anthracenediones [ e.g. mitoxantrone (MTX)] (Hrynchak et al ., 2017; Reis-Mendes et al ., 2015). DOX has been used for almost 50 years, but cardiotoxicity has been a critical and limiting side effect in its clinical use.…”