Synthesis and Characterisation of Novel 3-Chloropiperidine Derivatives as DNA Alkylating Agents

Abstract

With the advent of the 21st century, an epidemiological transition occurs in most developed nations, in which infectious diseases are gradually superseded by noncommunicable diseases such as cardiovascular disease and the neoplastic diseases. With an estimated 19.3 million new cases of malign neoplasm in 2020, there is an ever more increasing desire for novel therapeutic compounds and methods in oncology. Surgery and radiotherapy had dominated this medical domain until the 1960s, when cure rates plateaued at about 33% due to the presence of heretofore underrated micrometastases. Using chemotherapy in combination with radiotherapy and surgery proved to be the best strategy to tackle these more advanced malign neoplasms. Consequently, different important classes of chemotherapeutics emerged over the years, including alkylating agents, platinating agents, topoisomerase inhibitors, antimetabolites, intercalating agents and taxanes, of which the alkylating agents represent the oldest class of clinically used chemotherapeutics. The first documented therapeutic use of alkylating agents occurred in 1942, when Gilman and Phillips administered mechlorethamine, a structural derivative of sulfur mustard, to patients suffering from Hodgkin’s lymphoma. Even though the structure of DNA had yet to be elucidated by Franklin, Watson and Crick, Gilman and Phillips correctly proposed a mechanism considering alkylation of a vital cellular constituent. Over the years, scientists tried to develop milder and more selective analogues of the so called nitrogen mustards, which resulted in numerous compounds that are used clinically to this date, e.g. melphalan, chlorambucil and cyclophosphamide. The Göttlich group, inspired by nature, aimed to create simplified analogues of the naturally occurring nitrogen mustard 593A, an antibiotic with antineoplastic properties. Unlike previous synthetic nitrogen mustards, this compound features a 2-chloroethyl moiety confined in a piperidine ring, potentially offering a milder alternative to clinically used nitrogen mustards. The resulting bis-3-chloropiperidines and 3-chloropiperidines showed promising DNA alkylating capabilities, with certain derivatives being more active in cell studies towards the HCT-15 colon, the ovarian 2008 and the BxPC-3 pancreatic cancer cell line than reference compound chlorambucil. This work aims to elucidate the structure-activity-relationship (SAR) with a special focus on the geminal disubstituent effect in the formation of bicyclic systems, which could yield milder drugs in the future. Thereby, we observed a linear correlation between the inner angle of the C5-substituents in the piperidine ring and the rate constant of aziridinium ion formation, which suggests the presence of a classical Thorpe-Ingold-effect instead of a Reactive-Rotamer-effect. We furthermore developed an efficient, electroorganic protocol for the synthesis of 3-chloropiperidines, which resembles a substantial improvement in atom economy compared to existing methods as stoichiometric amounts of conventional oxidants can be avoided in the cyclization step. Biological assays revealed that bis-3-chloropiperidines show activity against the parasitic trematode Schistosoma mansoni and resemble a novel scaffold that can be considered in anthelmintic drug discovery.