Claude Monneret

Etoposide: Discovery and Medicinal Chemistry

Etoposide is an antitumor agent currently in clinical use for the treatment of small cell lung cancer, testicular cancer and lymphomas. Since the introduction of etoposide in 1971, its mechanism of action and potent antineoplastic activity has served as the impetus for intensive research activities in chemistry and biology. This drug acts by stabilizing a normally transient DNA-topoisomerase II complex, thus increasing the concentration of double-stranded DNA breaks. This phenomenon triggers mutagenic and cell death pathways. The function of topoisomerase II is understood in some detail, as is the mechanism of inhibition of etoposide at a molecular level. Etoposide has shortcomings of limited neoplastic activity against several solid tumors such as non-small cell lung cancer, cross-resistance to MDR tumor cell lines and low bioavailability. The design and synthesis of etoposide analogs is an activity of fundamental interest to the field of cancer chemotherapy. In the first part, this article is a survey of the discovery of etoposide, the DNA topoisomerase II structure and mechanism, and the models for drug-enzyme interaction. The last part is concerned with the search for new etoposide analogs based upon an empirical design.

Recent developments in the field of antitumour anthracyclines.

The anthracycline antibiotics daunorubicin (1) and doxorubicin (2) have been introduced in clinical use for more than 30 years for the treatment of a wide variety of cancers such as acute myeloid leukaemia, and, in the case of doxorubicin, a diversity of solid tumours [1]. Used as single agents or in combination therapy, they are the components of adjuvant, curative, as well as palliative treatments. Despite their extensive clinical utilisation, their mechanism of action has been the subject of controversy. A critical evaluation of these has recently been proposed [2] according to which these multiple mechanisms may be in fact related to the utilisation of drug concentration under varied experimental conditions. Nevertheless, two data seem to be formerly established: the first is that at drug concentration reflecting plasma concentration after bolus administration, the mechanism of drug action is likely to be through interaction with topoisomerase II by stabilisation of the ternary complex between DNA–topoisomerase II–drug [3]. The second is related to the mechanism of the cumulative cardiotoxicity of anthracyclines leading to congestive heart failure [4, 5] with, consequently, maximum recommended cumulative DNR and DOX doses of 500 and 450–600 mg m, respectively. In addition to this factor which limits the optimal effectiveness of DNR and DXR, another limitation is the development of spontaneous and acquired resistance (vide infra). Therefore, intensive researches to find new analogues have been developed by either biosynthetic studies or syntheses. Biosynthetic studies have led to more than 300 new compounds [6] whereas more than 2000 analogues were issued from structural modifications of natural compounds or from total syntheses [7–9]. Among them, one can cite as marketed drugs carminomycin (or carubicin) (3), produced by a strain of Actinomadura carminata, originally developed [10] in the Soviet Union in the 1980s, Aclacinomycin A (or aclarubicin) (4), the only class II anthracycline [11, 12] to have been once marketed both in France and Japan for the treatment of leukaemia, daunorubicin benzoylhydrazone

Synthesis of deoxy analogs of HEPT involving a palladium (0) catalyzed coupling

Abstract Deoxy analogs of HEPT (4–7) were prepared by Pd(0) catalyzed coupling between 6-(phenylthio)thymine and cinnamyl acetate or 3-(heteroaryl) allyl acetates.

Glucuronide prodrugs of hydroxy compounds for antibody directed enzyme prodrug therapy (ADEPT) : A phenol nitrogen mustard carbamate

Abstract A prodrug consisting of a β-D-glucuronic acid linked to a self-immolative spacer (a N-( ortho -hydroxyphenyl)-N-methylcarbamate) and a phenolic nitrogen mustard was synthesised. As this prodrug was easily cleaved by a β-glucuronidase enzyme and displayed low cytotoxicity, it must be considered as appropriate for an ADEPT approach.

A new acivicin prodrug designed for tumor-Targeted delivery

Acivicin is an antitumor agent known to inhibit cell growth. A new prodrug 9b of acivicin 10 was synthesized, based on a p-hydroxybenzylcarbamate self-immolative spacer capable to release acivicin under esterase activity. The prodrug includes a maleimide-containing arm for linkage with thiol-containing macromolecules such as antibodies. This molecule is intended for the conception of bioconjugates to target an inactive acivicin precursor to tumor cells, when linked to a monoclonal antibody (mAb) which recognizes a tumor-specific antigen. Prodrug cleavage by plasmatic esterases will then restore the acivicins activity toward tumor cells. We report here the synthesis and the in vitro characteristics of the prodrug. As expected, its inhibitory activity against the gamma-glutamyl transpeptidase (gamma-GT) enzyme and its cytotoxicity towards HL-60 cells were highly reduced compared to the parent drug. The chemical and plasmatic hydrolysis kinetics of the compound was studied by HPLC. The prodrug is stable, being slowly hydrolyzed in pH 7.6 buffer at 37 degrees C with a half-life of 37 h. It is converted into an active acivicin under the effect of pig liver esterase, and its half-life in human plasma is 3 h. These results indicate this compound may be further used as a prodrug-antibody conjugate, to target acivicin to malignant cells.

Synthesis of novel targeted pro-prodrugs of anthracyclines potentially activated by a monoclonal antibody galactosidase conjugate (part 1)

Abstract Daunorubicin substituted at N-3′ with a benzyloxycarbonyl group (self-immolative spacer) linked to an α-D-galactosyl residue such as 7a and 7b have been prepared as prodrugs. Conversion of 7a and 7b to daunorubicin will be mediated by an immunoconjugate consisting of an α-D-galactosidase enzyme covalently attached to a tumor specific monoclonal antibody.

Synthesis of 1-(3-R-amino-4-hydroxy butyl)thymine acyclonucleoside. Analogs as potential anti-aids drugs

Abstract The 1-(3-R-amino-4-hydroxybutyl)thymine acyclonucleoside analogs 8 – 12 , 14 , 16 , 19 , and the corresponding 3-aminomethyl derivatives 24 – 26 were prepared from the din-butyl ester of R-(−)-aspartic acid.

Synthesis and biological evaluation of vinylogous combretastatin A-4 derivatives

Stereospecific syntheses of the Z-E and E-Z vinylogues of combretastatin A-4, and two B-ring related analogues, were achieved through a Suzuki-Miyaura coupling. As compared to CA4, the derivative with a phenyl moiety has shown increased potency in its ability to inhibit tubulin polymerisation.

A rapid access to chiral alkylidene cyclopentenone prostaglandins involving ring-closing metathesis reaction

A synthesis of the alkylidene cyclopentenone prostaglandin TEI 9826 has been realized. The synthesis involved the preparation of the chiral 1,5-diene 8 using a stereoselective Claisen rearrangement from the allylic alcohol 6 giving the ester 7 after vinylation. Then a key RCM reaction allowed the preparation of the cyclopentenol 9 which, after oxidation, gave the cyclopentenone 10, precursor of the prostaglandin.

Prodrug Mono therapy: Synthesis and biological evaluation of an etoposide glucuronide-prodrug

A glucuronide-based prodrug of etoposide has been synthesized for a Prodrug Mono Therapy strategy. The aim is to selectively liberate the active compound by beta-D-glucuronidase already present in necrotic tumours. Outside from these sites, this enzyme is known to be localised inside the lysosomes. The three components of this prodrug are the glucuronic acid (substrate of the enzyme), the spacer (for a faster cleavage), and the active etoposide. In vitro, the prodrug was shown to be less cytotoxic and more water-soluble than etoposide itself. Finally, in the presence of the beta-D-glucuronidase, cleavage of the prodrug with complete release of the drug has been observed.