Dihydropyridine Derivatives to Overcome Atypical Multidrug Resistance: Design, Synthesis, QSAR Studies, and Evaluation of Their Cytotoxic and Pharmacological Activities

Mehdipour, Ahmad Reza; Javidnia, Katayoun; Hemmateenejad, Bahram; Amirghofran, Zahra; Miri, Ramin

doi:10.1111/j.1747-0285.2007.00569.x

Cited by 32 publications

(26 citation statements)

References 21 publications

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“…A similar effect may also be observed after felodipine treatment, which indicates that felodipine inhibits Aurora A in the cellular system. MLN8054 induces 82% spindle abnormality (26), whereas felodipine can induce a maximum spindle abnormality of 40%. Felodipine was found to be cytotoxic, which may be attributed to its dihydropyridine scaffold.…”

Section: Discussionmentioning

confidence: 95%

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool

Dhanasekaran

Siddhanta

Kishore

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We demonstrate the use of surface-enhanced Raman spectroscopy (SERS) as an excellent tool for identifying the binding site of small molecules on a therapeutically important protein.As an example, we show the specific binding of the common antihypertension drug felodipine to the oncogenic Aurora A kinase protein via hydrogen bonding interactions with Tyr-212 residue to specifically inhibit its activity. Based on SERS studies, molecular docking, molecular dynamics simulation, biochemical assays, and point mutation-based validation, we demonstrate the surface-binding mode of this molecule in two similar hydrophobic pockets in the Aurora A kinase. These binding pockets comprise the same unique hydrophobic patches that may aid in distinguishing human Aurora A versus human Aurora B kinase in vivo. The application of SERS to identify the specific interactions between small molecules and therapeutically important proteins by differentiating competitive and noncompetitive inhibition demonstrates its ability as a complementary technique. We also present felodipine as a specific inhibitor for oncogenic Aurora A kinase. Felodipine retards the rate of tumor progression in a xenografted nude mice model. This study reveals a potential surface pocket that may be useful for developing small molecules by selectively targeting the Aurora family kinases.vibrational spectroscopy | structure-activity relationship | ligand binding U nderstanding the mechanism of ligand binding to proteins is imperative for designing new molecules or screening potential drug molecules from available databases. We have used surface-enhanced Raman spectroscopy (SERS), which is a highly sensitive technique, to understand the binding of the commonly used hypertension drug, felodipine, to Aurora A kinase. Although NMR (1), X-ray crystallography (2), surface plasmon resonance (3), and fluorescence (4) are experimental techniques used to explore protein-drug interactions and each of these techniques provides unique information about the proteinligand interaction, a common problem of these techniques is the requirement of a high-protein concentration or the incorporation of secondary tagged molecules and a protein size limit. SERS has been traditionally used for the ultrasensitive detection of analytes. However, it can also be used to examine the protein-small molecule interactions and elucidate the mechanism (5-7). A commonly debated aspect is that SERS does not provide complete vibrational information compared with resonant Raman or normal Raman spectroscopy. Despite the limited information from SERS, which can be performed in proteins at extremely low concentrations in their active state, the competitive binding versus noncompetitive binding and specific changes in protein upon ligand binding can be explained. This approach is extremely effective when combined with molecular dynamics (MD) simulations and the structural information of the protein. The usefulness of this combination is that drugs can be screened for therapeutic applications. This paper provid...

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Section: Discussionmentioning

confidence: 95%

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool

Dhanasekaran

Siddhanta

Kishore

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Test compound-induced relaxation of the contracted muscle was expressed as percent of control. The IC 50 values were graphically determined from the contraction-response curve [36][37][38].…”

Section: Synthesis Of Asymmetrical 14-dhps (General Method)mentioning

confidence: 99%

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

Shahrisa

Zirak

Mehdipour

et al. 2011

Chem Heterocycl Comp

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were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC 50 =1.40×10 -7 M) with respect to the reference drug Nifedipine. The 4-aryl-substituted 1,4-dihydropyridines (1,4-DHPs) are among the most studied heterocyclic compounds that present interesting pharmacological and biological properties [1-4]. They have been used as organic calcium channel modulators [5-7], anticonvulsant [8], antidiabetic [9], antiviral [10], radioprotective [11], antitumor [12], antioxidant [13], vasodilator [14], and anti-inflammatory agents [15]. It was proposed that calcium channel modulation depends on the absolute configuration at C-4 and flexibility of both the ester group of 1,4-DHPs and the C-4 aryl group of these compounds [16,17]. Therefore, the development of new synthetic methods leading to 1,4-DHPs with different substituents [18−20] or heterocycles [21][22][23][24][25][26][27] has attracted much attention in organic synthesis. The Hantzsch synthesis is a classical method for the preparation of 1,4-DHPs [28] and has been one of the most important basic reactions in organic chemistry for its use in pharmaceutical synthesis. However, due to the drastic reaction conditions, long reaction times, and low yields, the classical Hantzsch reaction was modified by several methods [29].

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“…Med Chem Res (2011) Cytotoxicity assay Cell viability following exposure to synthetic compounds was estimated by using the MTT reduction assay (Mehdipour et al, 2007;Jabbar et al, 1989;Miri et al, 2004). MCF-7 and Raji cells were plated in 96-well microplates at a density of 5 9 10 4 cells/ml (100 ll per well).…”

Section: Experimental Protocolsmentioning

confidence: 99%

Synthesis and cytotoxic activity of novel benzopyrano[3,2-c]chromene-6,8-dione derivatives

et al. 2010

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4-Hydroxycoumarins constitute the structural nucleus of many natural products, drugs, and pesticides. Promising biological properties in new families of synthetic coumarins were recently reported. Therefore, efficient synthesis of new benzopyrano[3,2-c]chromene-6,8-dione was undertaken and the structures of 15 compounds were confirmed by their IR, Mass, 1 H-NMR, and C, H, N analysis. Then, the cytotoxic activities of these compounds were assessed on four different human cancer cell lines (Raji, HeLa, LS180, and MCF-7). The results showed that these compounds had weak-to-moderate antitumoral activities and their IC 50 ranged from 49 to more than 100 lM. Among the compounds 9,10-dihydro-7-(3-methoxyphenyl)-7H,11H-benzopyrano[3,2-c]chromene-6,8-dione [4k] demonstrated the highest activity. Furthermore, conformational analysis revealed that ortho substituents were clearly different from meta and para substituents.

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Dihydropyridine Derivatives to Overcome Atypical Multidrug Resistance: Design, Synthesis, QSAR Studies, and Evaluation of Their Cytotoxic and Pharmacological Activities

Cited by 32 publications

References 21 publications

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool

SERS and MD simulation studies of a kinase inhibitor demonstrate the emergence of a potential drug discovery tool

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

Synthesis and cytotoxic activity of novel benzopyrano[3,2-c]chromene-6,8-dione derivatives

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