Affinity of Macrocyclic Pyridinophanes and Their Acyclic Analogs to Peripheral Benzodiazepine CNS Receptors

Abstract

Previously [1], macrocyclic pyridinophanes (MCPs), representing macroheterocycles with pyridine fragments in the ring, were reported to exhibit antiviral properties. Recently [2], it was established that MCPs and their acyclic analogs are capable of inhibiting the growth of some malignant human tumors in vitro. We have suggested that one possible mechanism of the antitumor action of these compounds is related to their ability to bind to peripheral benzodiazepine receptors (PBDRs). PBDRs are involved in calcium homeostasis [3], mitochondrial steroidogenesis [4] and oxidation [5], cell proliferation [6], and immune system regulation [7]. There are numerous data indicating that PBDR density increases in cases of various brain tumors, breast cancer, ovarian cancer, etc. [8 – 11]. Clinical investigations performed in the past decade showed that the level of PBDR-immunoreactive cells in tumors correlates with the cell lifetime [12]. It was suggested to use PBDRs for recognizing tumors, localizing tumor boundaries, and determining the direction of metastasis [13]. Finally, PBDRs can be considered as a new intracellular target for selective antitumor drugs representing PBDR ligands [11]. This work is aimed at studying the affinity of PBDR to a series of macrocyclic Schiff bases representing derivatives of 2,6-bis(2and 4-formylaryloxymethyl)pyridines and their acyclic analogs (1 – 18, Fig. 1). All compounds were synthesized at the Bogatskii Institute of Physical Chemistry (Odessa).