Hydroxamic Acids Containing a Bicyclic Pinane Backbone as Epigenetic and Metabolic Regulators: Synergizing Agents to Overcome Cisplatin Resistance

SIMPLE SUMMARY: Chemotherapy is one of the most widely used cancer treatments. A significant barrier to its successful use is the high risk of acquiring the phenomenon of multidrug resistance in cancer. In this regard, today, researchers’ attention is focused on solving this critically important problem. In our work, the approach of using hydroxamic acids containing a para-substituted cinnamic acid core and bearing bicyclic pinane scaffolds, including derivatives of (−)-myrtenol, (+)-myrtenol and (−)-nopol, as a Cap-group is considered to be one of the possible solutions to this problem. Being modulators of epigenetic function and the metabolic state of neoplastic cells, 18c synergizes with cisplatin to increase the anticancer effect of cytostatic agent, and it overcomes cisplatin. ABSTRACT: Multidrug resistance is the dominant obstacle to effective chemotherapy for malignant neoplasms. It is well known that neoplastic cells use a wide range of adaptive mechanisms to form and maintain resistance against antitumor agents, which makes it urgent to identify promising therapies to solve this problem. Hydroxamic acids are biologically active compounds and in recent years have been actively considered to be potentially promising drugs of various pharmacological applications. In this paper, we synthesized a number of hydroxamic acids containing a p-substituted cinnamic acid core and bearing bicyclic pinane fragments, including derivatives of (−)-myrtenol, (+)-myrtenol and (−)-nopol, as a Cap-group. Among the synthesized compounds, the most promising hydroxamic acid was identified, containing a fragment of (−)-nopol in the Cap group 18c. This compound synergizes with cisplatin to increase its anticancer effect and overcomes cisplatin resistance, which may be associated with the inhibition of histone deacetylase 1 and glycolytic function. Taken together, our results demonstrate that the use of hydroxamic acids with a bicyclic pinane backbone can be considered to be an effective approach to the eradication of tumor cells and overcoming drug resistance in the treatment of malignant neoplasms.