Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4

Callophycin A was originally isolated from the red algae Callophycus oppositifolius and shown to mediate anticancer and cytotoxic effects. In our collaborative effort to identify potential chemopreventive and anticancer agents with enhanced potency and selectivity, we employed a tetrahydro-β-carboline-based template inspired by callophycin A for production of a chemical library. Utilizing a parallel synthetic approach, 50 various functionalized tetrahydro-β-carboline derivatives were prepared and assessed for activities related to cancer chemoprevention and cancer treatment: induction of quinone reductase 1 (QR1) and inhibition of aromatase, nitric oxide (NO) production, tumor necrosis factor (TNF)-α-induced NFκB activity, and MCF7 breast cancer cell proliferation. Biological results showed that the n-pentyl urea S-isomer 6a was the strongest inducer of QR1 with an induction ratio (IR) value of 4.9 at 50 μM [the concentration to double the activity (CD) = 3.8 μM] and its corresponding R-isomer 6f had an IR value of 4.3 (CD = 0.2 μM). The isobutyl carbamate derivative 3d with R stereochemistry demonstrated the most potent inhibitory activity of NFκB, with the half maximal inhibitory concentration (IC50) value of 4.8 μM, and also showed over 60% inhibition at 50 μM of NO production (IC50 = 2.8 μM). The R-isomer urea derivative 6j, having an appended adamantyl group, exhibited the most potent MCF7 cell proliferation inhibitory activity (IC50 = 14.7 μM). The S-isomer 12a of callophycin A showed the most potent activity in aromatase inhibition (IC50 = 10.5 μM).

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“…8 More importantly for our research, several tetrahydro- β -carboline derivatives have also been investigated as anticancer agents. 2,9 …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents

Shen

Park

Kondratyuk

et al. 2011

Bioorganic & Medicinal Chemistry

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“…For example the orally active small molecule PD0332991, which induces G 1 arrest in primary myeloma cells, prevents tumor growth by specific inhibition of CDK4/6 and is now in Phase 2 clinical trials [28], [29]. The natural compound fascaplysin (Figure 1), originally isolated from the sponge Fascaplysinopsis Bergquist [30], is a kinase inhibitor with enticing selectivity for CDK4 (IC 50 ∼0.4 µM) relative to the close homolog CDK2 (45% sequence identity, IC 50 ∼500 µM), and also shows approximately eightfold selectivity over CDK6 (68% sequence identity, IC 50 ∼3.4 µM) [31]. Approximating the dissociation constant K D with IC 50 and using the relation ΔG 0 = −RTlnK D , the difference in the free energy of binding between the CDK4/fascaplysin and CDK2/fascaplysin complexes can be calculated to 4.2 kcal/mol.…”

Section: Introductionmentioning

confidence: 99%

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

2012

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Cyclin-dependent kinases (CDKs) play a key role in the cell cycle and are important anti-cancer drug targets. The natural product fascaplysin inhibits CDK4 with surprising selectivity (IC50 = 0.4 µM) compared to the close homolog CDK2 (IC50 = 500 µM). Free energy calculations of the positively charged fascaplysin and an uncharged iso-electronic derivative in the CDK2 and CDK4 inhibitor complexes indicate that the positive charge of fascaplysin is crucial for selectivity. This finding will guide further improvements in the design of fascaplysin-based selective inhibitors for CDK4.

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“…6 Moreover, certain tadalafil related analogues have shown tumor cell growth inhibitory properties versus colorectal HT-29 cancer cell line that appear to be associated with their ability to inhibit PDE5. 7 Other reports have revealed anticancer activities to various tetrahydro- β -carbolines through different mechanisms, including inhibition of topoisomerase II, 8 cyclin dependent kinases, 9 and mitotic kinesin Eg5. 10 These observations suggest that tadalafil can serve as a good starting point for the discovery of novel anticancer compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

et al. 2010

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New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from L-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.

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Design, synthesis and biological evaluation of new tryptamine and tetrahydro-β-carboline-based selective inhibitors of CDK4

Cited by 57 publications

References 28 publications

Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents

Design, synthesis, and biological evaluation of callophycin A and analogues as potential chemopreventive and anticancer agents

FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

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