Search

For the first time, derivatives of 3,7-diazabicyclo[3.3.1]nonane (bispidine) were proposed as potential inhibitors of the SARS-CoV-2 main viral protease (3-chymotrypsin-like, 3CLpro). Based on the created pharmacophore model of the active site of the protease, a group of compounds were modeled and tested for activity against 3CLpro. The 3CLpro activity was measured using the fluorogenic substrate Dabcyl-VNSTLQSGLRK(FAM)MA;the efficiency of the proposed approach was confirmed by comparison with literature data for ebselen and disulfiram. The results of the experiments performed with bispidine compounds showed that 14 compounds exhibited activity in the concentration range 1-10 μM, and 3 samples exhibited submicromolar activity. The structure-activity relationship studies showed that the molecules containing a carbonyl group in the ninth position of the bicycle exhibited the maximum activity. Based on the experimental and theoretical results obtained, further directions for the development of this topic were proposed. ©

Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one, BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride, BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester, BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 &micro, M&ndash, 100 &micro, M) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 &micro, M, 23.7 &micro, M, and 36.3 &micro, M, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.

It is demonstrated that new lipid-like amphiphilic compounds, derivatives of 3,7-diazabicyclo[3.3.1]nonan-9-one (bispidinone) with long alkyl substituents, can be integrated into liposomal membranes. They can serve as molecular switches changing the conformation from the chair–boat to chair–chair on addition of an aqueous solution of a bivalent copper salt, and thus enhancing the permeability of the lipid bilayer of liposomes and the release of encapsulated compounds.

An effective synthesis which provides facile access to highly rigid tetraazamacrocycles possessing labile functional groups is reported. Essential to the approach is bis-bispidinone, a versatile substrate which can be prepared from an unusually stable bispidine diethyl ketal building block and requires a non-aqueous isolation process. Further functionalization of the substrate allows direct and concurrent incorporation of functionalities onto the bis-bispidine tetraazamacrocyclic framework, in particular those that are labile during the macrocycle formation.

A linear synthesis, a convergent synthesis and cyclic Mannich reactions were used to prepare the macrocyclic bispidinone ionophores (6–7), (14) and (12–13). The convergent synthesis required successful alkylation of the N -unsubstituted bispidinone (9).

In the solid state bispidinone 4 exists in a CB conformation and in solution undergoes rapid degenerate interconversion CB←→BC as revealed by variable temperature 1H and 13C NMR studies.

The chapter of the third edition of Comprehensive Heterocyclic Chemistry (CHEC III) 12.24 titled ‘Eight-membered Rings with two Heteroatoms 1,5’ deals with diheterocines rings with two heteroatoms in a 1,5 relationship, namely 1,5-diazocine, 1,5-oxazocine, 1,5-thiazocine, 1,5-dioxocin, 1,5-oxathiocin, and 1,5-dithiocin. This chapter covers the literature from 1996 to 2006 and also reports those articles published in 1995 which were not reported in CHEC-II(1996). In this edition, in addition to the uncondensed derivatives, eight-membered 1,5-heterocycles fused to five-, six-, and seven-membered carbocycles or heterocycles are covered. Bridged diheterocines, which actually constitute the majority of the compounds reported were covered as well. The main change in this chapter, with respect to CHEC-II(1996), is related to the ‘Theoretical Methods’ section. Such a section in CHEC-II(1996) was a unique section, placed immediately after the introduction and dealt with all the classes of eight-membered heterocycles with two heteroatoms. In this edition, each section dealing with a single class of heterocycles has its own ‘theoretical methods’ section. The ‘Experimental Structural Methods’ section has received a strong impulse since, with some exceptions, the great majority of the reported derivatives have been adequately characterized. As already done in CHEC-II(1996), all six systems are discussed separately with each discussion following the same general format. In case particular sections are not mentioned, it means that no chemistry has been reported.

A crystal structure of the macrocyclic bispidinone 6 reveals a chair-boat conformation and a variable temperature 1H NMR study demonstrates that in solution this configuration is in a degenerate equilibrium.