Trials of phenanthrene opioids functionalization with hindered polycyclic carboxylic acids

Authors

Dipartimento di Chimica, Università di Roma “La Sapienza”, Rome, Italy

Abstract

In the last decades, the number of patients undergoing pain relief for chronic or degenerative diseases has observed a significant increase, also due to an increase in the average age of the population. Morphine, the widely used opioid in pain therapy, is known to produce over time tolerance with the appearance of hyperalgesia and allodynia, conditions which may affect patient compliance. These phenomena have been re-conducted to one of its metabolite, the 3-O-glucuronide (accounting in humans for 80% of the dose administered), which was found to be an effective neuro-excitatory and a potent activator of microglia, so resulting to be responsible of the development of both hyperalgesia and allodynia. Therefore, the inhibition of glucuronidation represents an interesting pharmacological target to achieve greater therapeutic efficacy by morphine and the synthesis of new active compounds useful in the pain control therapy is still in the limelight. In this context, we observed that codeine and some codeine derivatives (in particular the acetyl and pivaloyl esters) are able to inhibit the formation of morphine-3-O-glucuronide so, in continuation of the previous work, we projected new codeine derivatives as potential useful compounds in the modulation of morphine glucuronidation. In this paper, we report the optimization of the synthetic procedure to obtain codeine esters with hindered polycyclic carboxylic acids by using a suitable alcohol (allyl alcohol) with the same configuration of 6-OH function of the codeine skeleton. Together with the allyl ester derivatives of these acids also the 1-adamantaneacetic acid ester derivative of codeine (4), a new codeine derivative, was finally synthesized following the reported synthetic approach.

Graphical Abstract

Trials of phenanthrene opioids functionalization with hindered polycyclic carboxylic acids

Keywords


Angelova, P., Kostova, K., Hinrichs, K., Tsankov, D., 2005. A convenient synthesis of long-chain 4-substituted benzyloxycarbonyl alkanethiols for the formation of self-assembled monolayers on metal substrates. Cent. Eur. J .Chem. 3(4), 658-667.

Antonilli, L., Togna, A.R., Sabatini, G., Venditti, A., Guarcini, L., Togna, G.I., Nicoletti, R., Sanasai, F., Bianco, A., Nencini, P., 2013a. Pivaloylcodeine, a new codeine derivative, for the inhibition of morphine glucoronation. An in vitro study in the rat. Bioorg. Med. Chem. 21(24), 7955-7963.

Antonilli, L., Bianco, A., Guarcini, L., Nencini, P., Nicoletti, R., Togna, A.R., Togna, G.I., Venditti, A., 2013b. Derivati della codeina come inibitori della glucoronazione della morfina. Brevetto Italiano (Italian Patent) N° IT2013RM00223 20130415.

Elovaara, E., Mikkola, J., Stockmann-Juvala, H., Luukkanen, L., Keski-Hynnilä, H., Kostiainen, R., Pasanen, M., Pelkonen, O., Vainio, H., 2007. Polycyclic aromatic hydrocarbon (PAH) metabolizing enzyme activities in human lung, and their inducibility by exposure to naphthalene, phenanthrene, pyrene, chrysene, and benzo(a)pyrene as shown in the rat lung and liver. Arch. Toxicol. 81(3), 169-182.

Franceschin, M., Nocioni, D., Biroccio, A., Micheli, E., Cacchione, S., Cingolani, C., Venditti, A., Zizza, P., Bianco, A., Altieri, A., 2014. Design and synthesis of a new dimeric xanthone derivative: enhancement of G-quadruplex selectivity and telomere damage. Org. Biomol. Chem. 12(47), 9572-9582.

Gibson, F.S., Park, M.S., Rapoport, H., 1994. Bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl]-carbodiimmide (BDDC) and its application to residue-free esterifications, peptide couplings, and dehydrations. J. Org. Chem.  59(24), 7503-7507.

Graziottin, A., Gardner-Nix, J., Stumpf, M., Berliner, M.N., 2011. Opioids: how to improve compliance and adherence. Pain Pract. 11(6), 574-581.

Hassner, A., Vazken, A., 1978. Direct room temperature esterification of carboxylic acids. Tetrahedron Lett. 19(46), 4475-4478.

Höfle, G., Steglich, W., Vorbrüggen, H., 1978. 4-Dialkylaminopyridines as highly active acylation catalysts. Ang. Chem. Int. (English Ed) 17(8), 569-583.

Komatsu, T., Sakurada, S., Katsuyama, S., Sanai, K., Sakurada, T., 2009. Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice. Int. Rev. Neurobiol.  85, 207-219.

Leonelli, F., La Bella, A., Francescangeli, A., Joudioux, R., Capodilupo, A.L., Quagliariello, M., Migneco, L.M., Marini Bettolo, R., Crescenzi, V., 2005. A new and simple available class of hydrosolubles bioconjugates by coupling paclitaxel to hyaluronic acid trough a 4-hydroxybutanoic acid derived linker. Helv. Chim. Acta 88(1), 154-159.

Lewis, S.S., Hutchinson, M.R., Rezvani, N., Loram, L.C., Zhang, Y., Maier, S.F., Rice, K.C., Watkins, L.R., 2010. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 165(2), 569-583.

Milne, R.W., Nation, R.L., Somogyi, A.A., 1996. The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine. Drug Metab. Rev. 28(3), 345-372.

Ornano, L., Feroci, M., Guarcini, L., Venditti, A., Bianco, A., 2018. Anti-HIV agents from nature: natural compounds from Hypericum hircinum and carbocyclic nucleosides from iridoids. Stud. Nat. Prod. Chem. 56, 173-228.

Salemme, A., Togna, A. R., Mastrofrancesco, A., Cammisotto, V., Ottaviani, M., Bianco, A., Venditti, A., 2016. Anti-inflammatory effects and antioxidant activity of dihydroasparagusic acid in lipopolysaccharide-activated microglial cells. Brain Res. Bull. 120, 151-158.

Smith, H.S., 2009. Opioid Metabolism. Mayo Clin. Proc. 84(7), 613-624.

Venditti, A., Mandrone, M., Serrilli, A. M., Bianco, A., Iannello, C., Poli, F., Antognoni, F., 2013. Dihydroasparagusic acid: antioxidant and tyrosinase inhibitory activities and improved synthesis. J Agric. Food Chem. 61(28), 6848-6855.

Venditti, A., Lorenzetti, L.M., Frezza, C., Serafini, M., Ornano, L., Bianco, A., 2017. Semi-synthesis of three precursors of carbocyclic nucleoside analogues. Trends Org. Chem. 18, 101-105.

Watkins, L.R., Hutchinson, M.R., Johnston, I.N., Maier, S.F., 2005. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci. 28(12), 661-669.