Anti-Neoplastic Activity of 1,3-Diaza-2-Functionalized-Adamantan-6-One Compounds Against Melanoma Cells

Abstract

Four series of 1,3-diaza-2-functionalized-adamantan-6-one derivatives, bearing at the 2 position SO, SO₂, POCl and PO₂H functional groups, were synthesized via a key quadruple Mannich reaction, followed by transformation of an aminal functionality into the final 2-thia- and 2-phospha compounds. The compounds were tested for cytotoxic activity against the mouse B16-F10 melanoma cell line. Malignant melanoma is notorious for its high resistance to chemotherapy, and new anti-melanoma drugs are urgently needed. The 2-thia compounds exhibited poor proliferation inhibition activity, but the 2-phospha derivatives showed significant activity, with IC₅₀ values of 10-60 µM. The compounds induced cell death by G₂/M cell cycle arrest, which led to apoptosis, as determined by Annexin V-FITC/PI staining, mitochondrial membrane potential changes assessed by the JC-1 reagent, caspases 3 and 7 activation, and morphological changes.

Azaadamantanes, a New Promising Scaffold for Medical Chemistry

“…The synthesis and study of the antitumor activity of several series of 2-thio- and 2-phospho-containing 1,3-diazaadamantanes ( Fig. 13 ) against mouse melanoma cells B16-F10 were carried out by Sharabi-Ronen et al [ 49 ]. According to the authors, 2-thio-containing 1,3-diazaadamantanes ( 124 ) and ( 125 ) showed low activity against tumor cells (IC 50 > 200 µM).…”

“…According to the authors, 2-thio-containing 1,3-diazaadamantanes ( 124 ) and ( 125 ) showed low activity against tumor cells (IC 50 > 200 µM). More promising results were obtained for phosphorus-containing analogs ( 126 ) and ( 127 ), which showed significant antitumor activity (IC 50 = 10–60 µM) [ 49 ]. In addition to the cytotoxicity of the resulting compounds, the authors studied the influence of the most active 5,7-di(4-(trifluoromethyl)benzyl-1,3-diaza-2-phosphoadamantanes ( 126 ) and ( 127 ) on the cell cycle and the activation of apoptosis.…”

Theoretical Study on Molecular Structure and Electronic Properties of New 1,3-Diaza-adamantan-6-ones Derivatives

“…Among these derivatives, 1,3-Diaza-adamantane derivatives have attracted great attention due to their interesting properties [9] such as antibacterial, and psychotropic activity [10][11]. Sharabi-Ronen et al have reported the anti-neoplastic activity of 1,3-Diaza-2-functionalized-adamantan-6-one compounds against melanoma cells [12]. They showed that the ability of the reported compounds to introduce apoptosis in melanoma cells was significant.…”