Michael Rivard

In the presence of amines, the degradation of glutaconaldehyde in acidic medium can be prevented. By exploitation of this behavior, primary amines are transformed into their corresponding pyridinium salts, including those substrates that remain unreactive toward the Zincke salt, which is the reagent typically used to perform this transformation. The use of glutaconaldehyde also allows control of the nature of the counterion of the pyridinium with no need for additional salt metathesis reaction.

Interest in the therapeutic effects of carbon monoxide (CO), a product of heme degradation catalyzed by the enzyme heme oxygenase‐1 (HO‐1), has led to the development of CO‐releasing molecules (CO‐RMs) for the controlled delivery of this gas in vivo. We recently proposed conjugating a cobalt‐based CO‐RM with various activators of nuclear factor erythroid 2‐related factor 2 (Nrf2), the transcription factor that regulates HO‐1 expression, in order to exploit the beneficial effects of exogenous and endogenous CO. In this study, we describe the preparation of hybrid molecules (termed HYCOs) conjugating a fumaric acid derivative as an Nrf2 activator to a Mn‐ or a Ru‐based CO‐RM known to be pharmacologically active. With the exception of an acyl‐manganese complex, these hybrids were obtained by associating the two bioactive entities by means of a linker of variable structure. X‐ray diffraction analyses and preliminary biological investigations are also presented.

The Zincke reaction poses a difficulty when attempting to purify the crude mixtures and isolate reaction products in analytically pure form. This paper introduces the successful method of using the centrifugal partition chromatography (CPC) to isolate pyridinium salts garnered by this reaction returning good yields and high degrees of purity. Efficient purifications were obtained by using ( n ‐BuOH/MeOH/H ₂ O) biphasic solvent systems. The CPC confirmed its suitability for isolating compounds prone to decompose during purification on solid stationary phases. It has also proved to be an efficient method for valorizing incomplete Zincke reactions.

Morinda geminata DC is a plant of the traditional Senegalese pharmacopoeia, the leaves of which are used in the treatment of various diseases. The phytochemical investigation of its leaves and roots resulted in the isolation of the triterpenoid ursolic acid 6, and five known anthraquinones analogues: nordamnacanthal 1, damnacanthal 2, damnacanthol 3, lucidin-ω-ethyl ether 4, and anthraquinone 5. The isolated compounds were characterized by NMR and mass-spectrometry and were evaluated for their antimicrobial properties. Compounds 1 and 4 displayed significant antimicrobial activities towards Staphylococcus aureus. The present study constitutes the first phytochemical examination of the leaves and roots of Morinda geminata DC.

Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4⁺ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4⁺ T cells and CD8⁺ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the design of nano-immuno-conjugates (NICs) which could benefit of the immunomodulatory effects of X-Oxaza combined to their antiproliferative properties targeted through immune checkpoint antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Julia Delahousse, Charles Skarbek, Valentine Gauthier, M Desbois, Emilie Roger, C. Pioche-Durieu, M. Rivard, D. Desmaële, T. Martens, E. LeCam, Jean-Pierre Benoit, P. Couvreur, Nathalie Chaput-Gras, Angelo Paci. Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2195. doi:10.1158/1538-7445.AM2017-2195