Molecular Structure of 1‐Azaadamantanes and 1,3‐Diazaadamantanes

Jiménez-Cruz, Federico; Rı́os-Olivares, Héctor; Gutiérrez, José Luis García

doi:10.1002/chin.200702248

Cited by 2 publications

(3 citation statements)

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“…The negative hyper-conjugative effect of lone pair in the nitrogen atom toward the carbonyl contributed to the decrease in the N-C bond lengths. These results are in line with those observed in earlier studies by Jiménez-Cruz et al [18].…”

Section: ■ Computational Methodssupporting

confidence: 94%

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

2020

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In this study, the structural geometry and vibrational frequencies (IR) of 1,3-Diaza-adamantane-6-ones derivatives including Adamantane (A), 1,3-Diaza-adamantan (D), 1,3-Diaza-adamantan-6-one (DO), 5-Benzyl-1,3-diaza-adamantan-6-one (BD), 5-(4-Hydroxybenzyl)-1,3-diaza-adamantan-6-one (HBD), 5-(4-Methoxybenzyl)-1,3-diaza-adamantan-6-one (MBD), and 5-(4-Hydroxy-3-methoxybenzyl)-1,3-diaza-adamantan-6-one (HMBD) were theoretically studied. In addition, molecular orbital energies, including the highest occupied molecular orbitals (HOMOs), and lowest unoccupied molecular orbitals (LUMOs), and electronic properties of the titled molecules were theoretically studied using the computational method. Optimized molecular structures were obtained by DFT method with the hybrid B3LYP functional at a relatively small basis set of 6-31G. The calculated vibrational wavenumbers were obtained using the same level of the theory mentioned above. The contributions to the molecular orbitals of adamantane and substituted-phenyl groups in the title compounds were determined. Moving from A to HMBD, a decrease in the value of LUMO and total energy are noticed, while an increase in the value of HOMO is noted. These findings are supported by the decreasing in the EHOMO-LUMO gap values. Furthermore, a decrease in the value of ionization potential (IP) is obtained, while an increase in the electronegativity (EA) is observed.

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Section: ■ Computational Methodssupporting

confidence: 94%

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

2020

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“…(1-(4-Chloro-2-butenyl)-1l~5~,3,5,7tetraazatricyclo[3.3.1.1e3,7~]decane) that either alone or in combination potentiates 5-FU-mediated growth inhibition of CRC heterogeneous bulk, FOLFOX-resistant and CRC stem cells while maintaining the integrity of the normal colonic epithelial cells [13]. Nitrogen containing adamantane analogs [14,15], e.g., 1azaadamantanes, 1,3-diazaadamantanes, 1,3,5-triazaadamantanes and 1,3,5,7-tetraazaadamantanes are of great interest as conformationally constrained motifs for the design of various pharmacological tools [16]. Structural uniqueness of these azaadamantanes is related to both physical and chemical properties, most notably in the reduction of lipophilicity thus inducing higher aqueous solubility of these compounds compared to that of adamantanes consisting solely of carbon and hydrogen atoms [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Nitrogen containing adamantane analogs [14,15], e.g., 1azaadamantanes, 1,3-diazaadamantanes, 1,3,5-triazaadamantanes and 1,3,5,7-tetraazaadamantanes are of great interest as conformationally constrained motifs for the design of various pharmacological tools [16]. Structural uniqueness of these azaadamantanes is related to both physical and chemical properties, most notably in the reduction of lipophilicity thus inducing higher aqueous solubility of these compounds compared to that of adamantanes consisting solely of carbon and hydrogen atoms [14,15]. However, studies of the biological activity of azaadamantanes and their derivatives are still relatively less explored despite having good pharmacological properties.…”

Section: Introductionmentioning

confidence: 99%

ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells

Narayan

Ramisetti

Jaiswal

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tDespite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/ oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOXresistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased gH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.

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Molecular Structure of 1‐Azaadamantanes and 1,3‐Diazaadamantanes

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 2 publications

References 0 publications

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

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

ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells

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