Brigitte Renoux

The First Generation of β-Galactosidase-Responsive Prodrugs Designed for the Selective Treatment of Solid Tumors in Prodrug Monotherapy†

Massive attack: Galactoside prodrugs have been designed that can be selectively activated by lysosomal β-galactosidase located inside cancer cells expressing a specific tumor-associated receptor. This efficient enzymatic process triggers a potent cytotoxic effect, releasing the potent antimitotic agent MMAE and allowing the destruction of both receptor-positive and surrounding receptor-negative tumor cells.

β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update.

The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of β-glucuronidase-responsive albumin binding prodrugs.

Ring closing metathesis and cross metathesis of carbohydrate derivatives

Abstract In connection with the synthesis of annonaceous acetogenins and analogs, RCM of unsaturated esters has been studied with the Grubbs benzylidene carbene catalyst to give 9 to 15 membered lactones in moderate to good yield. Cross metathesis between 2 carbohydrate derivatives and methyl undec-10-enoate is also reported.

Synthesis and Antitumor Efficacy of a β-Glucuronidase-Responsive Albumin-Binding Prodrug of Doxorubicin

In this paper we describe the synthesis and biological evaluation of the first β-glucuronidase-responsive albumin-binding prodrug designed for the selective delivery of doxorubicin at the tumor site. This prodrug leads to superior antitumor efficacy in mice compared to HMR 1826, a well-known glucuronide prodrug of doxorubicin that cannot bind covalently to circulating albumin. Furthermore, this compound inhibits tumor growth in a manner similar to that of doxorubicin while avoiding side effects induced by the free drug.

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.

A self-immolative dendritic glucuronide prodrug of doxorubicin

The first self-immolative dendritic glucuronide prodrug of doxorubicin was studied with the aim to target β-glucuronidase overexpressed in the microenvironment of numerous tumors. This compound includes a chemical amplifier programmed to release two molecules of doxorubicin after a single enzymatic activation step. Upon β-glucuronidase activation, the dendritic prodrug was twice more toxic than its monomeric counterpart against H661 lung cancer cells.

A general and regiospecific route to tetracyclic alkenes in the 11-deoxyanthracyclinone series: application to the total synthesis of (±)-auramycinone

Abstract Starting from Hagemanns ester the preparation of new ketene acetals 4a and 4b and their cycloaddition with juglone derivatives to give ll-deoxytetracyclic alkenes 20 and 21 are described Furthermore the first total synthesis of(±)-auramycinone (8) has been completed from 20 in only nine overall steps from juglone.

Synthesis and cytotoxic activity of tetracenomycin d and of saintopin analogues

Regiospecific synthesis of title compounds is based either on cycloaddition of ketene acetals derived from Hagemanns ester or of homophthalic anhydrides. Thus, tetracenomycin D and 3,8-di-O-methyl saintopin have been prepared in few steps. New derivatives of 10-deoxysaintopin have been also obtained. Evaluation of their cytotoxicity against L1210 leukemia cells are reported.

A Heterodimeric Glucuronide Prodrug for Cancer Tritherapy: the Double Role of the Chemical Amplifier

Most anticancer drugs suffer from poor selectivity leading to severe side effects due to action against normal as well as diseased tissue. Thus, the development of drug carriers designed to deliver potent therapeutic agents exclusively at the tumor site has emerged as one of the great challenges in medicinal research. One promising targeting strategy relies on the use of nontoxic prodrugs that can be activated by an enzyme naturally overexpressed in the tumor microenvironment. In this approach, enzymatic prodrug activation is followed by the release of the parent drug thereby restoring its antitumor activity selectively in malignant tissues. Several enzyme-responsive prodrugs have already been evaluated in vivo with encouraging results. However, the relatively slow action and low concentration of all tumor-associated enzymes discovered so far represent the “Achilles’ heel” of such a targeting strategy. These unfavorable enzymatic parameters limit the amount of drug liberated in targeted tissues and therefore the efficacy of the treatment. To overcome this drawback, Shabat, de Groot and McGrath simultaneously introduced the concept of self-immolative dendrimers allowing the release of several drug units after a single triggering event, thanks to an efficient chemical amplification process. In an elegant study, the Shabat group also developed heterodimeric and heterotrimeric systems designed to deliver highly toxic drug cocktails with a single enzymatic activation step. Herein, we present the novel drug delivery device 1 designed for the selective targeting of three different cytotoxic agents (Scheme 1 a). This system is composed of five distinct units: an enzymatic trigger, a self-immolative linker and two potent anticancer drugs articulated around a chemical amplifier. Enzymatic cleavage of the trigger–linker bond generates intermediate 2, which then falls apart spontaneously giving rise to anticancer activity. In this study, we demonstrated for the first time that the chemical amplifier can play two crucial roles in the efficiency of this targeting strategy. First, the amplifier is responsible for signal amplification transforming a single enzymatic event into a double drug release. Second, in the course of this process, the amplifier is converted into a third highly toxic species that, combined with the two other drugs, leads to selective and potent cancer tritherapy. The device 1 was designed to simultaneously target two established agents: the widely used doxorubicin and the well known histone deacetylase inhibitor MS-275. As illustrated in Scheme 1 b, this heterodimeric prodrug includes a nitrobenzylphenoxy carbamate linker between the glucuronide trigger and amplifier unit. With this design, the enzyme substrate is located at a substantial distance from the two bulky drugs to allow easy recognition of 1 by b-glucuronidase. Thus, enzymecatalyzed cleavage of prodrug 1 should result in the release of phenol intermediate 2, which induces the release of aniline 3 through a 1,6-elimination process. Once turned on, the amplifier first causes the expulsion of doxorubicin via a 1,4-elimination followed by spontaneous decarboxylation. Addition of water to ortho-azaquinone methide 6 then generates aniline 7 thereby permitting the release of MS-275 along with the formation of derivative 8. As azaquinone methides are potential alkylating species, we anticipated that 8 could also be toxic toward cancer cells thus playing the role of a third antitumor agent. We chosen b-glucuronidase as the triggering enzyme since it has been detected in high levels in a wide range of malignancies, such as breast, lung, colon and ovarian carcinomas, as well as melanomas. Tietze was one of the first researchers to propose this tumor-specific enzyme as a target for selective therapy using nontoxic glucuronide prodrugs in the course of a prodrug monotherapy (PMT). Since then, several glucuronide prodrugs have been evaluated in vivo demonstrating superior efficacy compared to standard chemotherapy. The efficiency of this approach is, however, limited by the reduced turnover of b-glucuronidase in the tumor microenvironment. Indeed, the optimal pH for b-glucuronidase activity is around 4, whereas the pH of tumor extracellular media is 6–7. In this context, the use of novel targeting devices such as 1 should circumvent this problem through the release of several drug units after a single enzymatic hydrolysis. The synthesis of prodrug 1 was carried out starting from alcohol 9, previously described in the literature (Scheme 2). First, protecting groups of the carbohydrate moiety were modified via a five-step strategy to yield fully allyl-protected glucuronyl derivative 10. Protected in this way, the glucuronide can be entirely deprotected in the course of a one-step procedure under mild conditions at the end of the synthesis. Treatment of benzyl alcohol 10 with 4-nitrophenyl chloroformate and pyridine afforded activated carbonate 11 (84 %). Aniline 12 was introduced chemoselectively via nucleophilic [a] Dr. M. Grinda, Dr. I. Tranoy-Opalinski, Dr. B. Renoux, Dr. S. Papot Laboratoire de Synth se et R activit des Substances Naturelles UMR-CNRS 6514, Universit de Poitiers 4 rue Michel Brunet, BP 633, 86022 Poitiers (France) E-mail : sebastien.papot@univ-poitiers.fr [b] Dr. J. Clarhaut, Dr. A. Monvoisin, Dr. L. Cronier Institut de Physiologie et Biologie Cellulaires UMR-CNRS 6187, Universit de Poitiers 1 rue Georges Bonnet, BP 633, 86022 Poitiers (France) [c] Dr. J. Clarhaut INSERM CIC 0802 2 rue de la Mil trie, CHU de Poitiers, 86021 Poitiers (France) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201100355.

Gem-difluorination of aminoalkynes via highly reactive dicationic species in superacid HF-SbF5: application to the efficient synthesis of difluorinated cinchona alkaloid derivatives.

A variety of alkynylated amines, amides, and imides are reacted in the superacid system HF-SbF5 to give regioselectively new beta-gem-difluoroamines. The reaction, which is not observed in pure HF, is consistent with the formation of a dicationic intermediate (i.e., both vinylic and adjacent protonated N-ammonium cations). Application to the regioselective and efficient synthesis of difluorinated cinchona alkaloid derivatives is described.