A Green Approach to the Production of Hybrid Diindolylmethane-Phenylboronic Acids via a 3MCR: Promising Antineoplasic Molecules

Abstract

The current role of the “Green Chemistry Protocol” in multicomponent reactions is first highlighted. Then, the green approach to the production of three novel hybrid diindolylmethanes-phenylboronic acids via a 3MCR is discussed, which features the following: solventless conditions, the use of microwave irradiation to activate the reactions, the absence of catalyst, and an efficient atom economy. The products were achieved with moderate yields (41–61%) within a short time frame (5 min) and appropriately characterized by elemental analysis and spectroscopic methods (NMR:1H,13C,11B; MS: EI, CI, FAB+, HRMS). During the FAB+MS determinations, various artifacts that are associated with the boron atom via an interaction with thioglycerol from the matrix were noted in the corresponding FAB+mass spectra; in addition, the accurate mass determination of these adducts unequivocally confirmed the presence of the target molecules. Moreover, the activity of these target molecules was evaluated in the presence of six cancer cell lines (U251 = glia of the central nerve system, PC-3 = prostate, K562 = leukemia, HCT-15 = colon, MCF-7 = breast, and SKLU-1 = lung), which resulted in themeta-regioisomer being the most active. Finally, the products were also analyzed using computational chemistry in order to determine their most stable geometries and reactivities by computing the respective molecular electrostatic potentials.

A DFT Study of the Geometrical, Spectroscopical and Reactivity Properties of Diindolylmethane-Phenylboronic Acid Hybrids

“…The stability of ct - III molecule can be attributed to the lower steric effect. These stability results have been previously reported [ 12 ].…”

“…An interesting outcome was obtained from the corresponding theoretical study of the Nuclear Magnetic Resonance (NMR) chemical shifts for 1 H, 13 C and 11 B, both in gas phase and acetone solution. It should be mentioned that the corresponding experimental values of the chemical shifts for 1 H and 13 C have been previously reported by our research group [ 12 ], and these values were correlated with those calculated by DFT at the B3LYP level using the 6-311++G(d,p) basis set and the GIAO method ( Figure 8 ).…”

“…Since the experimental X-rays patterns of the target molecules have not been yet published, and considering the motifs present in these molecules [ 1 , 3 , 12 , 14 , 19 , 21 , 22 ], the obtained values were compared by the same motif previously reported in other compounds [ 14 , 19 , 20 ]. In this sense, the calculated values were agreed with the previously reported data, considering the structural differences with the reference molecules.…”

“…It is also convenient to highlight that modern synthetic chemists currently engage in the synthesis of hybrid molecules, which are made by combining appropriately pieces of different other molecules, in order to synergize or modify the pharmacological activity of the corresponding prototypes. As part of our ongoing research program, we are interested in green chemistry protocols for the production of novel hybrid heterocyclic molecules, and thus we recently reported the synthesis and biological evaluation of three relatively novel hybrid molecules I – III of diindolylmethane and phenylboronic acids [ 12 ]; it is important to note that the obtained results were indicative that the hybrid products were promising antineoplastic compounds. To this end the cytotoxic effects of the hybrid molecules were evaluated on six cancer cell lines (U251 = central nervous system glia, PC-3 = prostate, K562 = leukemia, HCT-15 = colon, MCF-7= breast, SKLU-1 = lung), which evidenced that the meta regioisomer was the most active [ 12 ].…”

“…As part of our ongoing research program, we are interested in green chemistry protocols for the production of novel hybrid heterocyclic molecules, and thus we recently reported the synthesis and biological evaluation of three relatively novel hybrid molecules I – III of diindolylmethane and phenylboronic acids [ 12 ]; it is important to note that the obtained results were indicative that the hybrid products were promising antineoplastic compounds. To this end the cytotoxic effects of the hybrid molecules were evaluated on six cancer cell lines (U251 = central nervous system glia, PC-3 = prostate, K562 = leukemia, HCT-15 = colon, MCF-7= breast, SKLU-1 = lung), which evidenced that the meta regioisomer was the most active [ 12 ]. Consequently, taking into account the importance of these compounds, we deemed it convenient to report the novel and interesting results of a theoretical study of the target compounds I – III .…”