Synthesis of novel spiro[pyrazolo[4,3- d ]pyrimidinones and spiro[benzo[4,5]thieno[2,3- d ]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

Ismail, Ismail; Bhaskar, K.; Thalari, Gangadhar; Bommarapu, Venkatesham; Mulakayala, Chaitanya; Chitta, Suresh Kumar; Mulakayala, Naveen

doi:10.1016/j.bmcl.2017.01.088

Cited by 28 publications

(7 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other than that, only few specific Sirt1 inhibitors have been identified. Several examples with low micro molar affinity exist, like certain Splitomicin derivatives or the so-called spiro series (52,53). To get more insights into the role of Sirt1 in different cancer types and to better examine its therapeutic potential in cancer further Sirt1 inhibitors are needed.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

et al. 2020

View full text Add to dashboard Cite

Sirtuin 1 (Sirt1) is a NAD + dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC 50 of 13 µM. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 µM IC 50) were further studied in cells. The ratio of phosphorylated γH2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered γH2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In Wössner et al. Sirtuin 1 Inhibiting Thiocyanates (S1th) addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.

show abstract

Section: Introductionmentioning

confidence: 99%

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Isobavachalcone is the major constituent extracted from Fructus psoraleae, which presents versatile effects including antitumor [ 59 , 60 ], antibacterial [ 61 ], and bone strengthening [ 62 ] effects. A study showed that isobavachalcone could recede the LPS-induced oxidative stress and inflammatory cytokine levels and that it possessed an effect of neuroprotection by inhibiting microglia-mediated inflammation [ 63 ].…”

Section: Herbal Compoundsmentioning

confidence: 99%

Herbal Compounds Play a Role in Neuroprotection through the Inhibition of Microglial Activation

Jin

Wang

et al. 2018

Journal of Immunology Research

View full text Add to dashboard Cite

Since microglia possess both neuroprotective and neurotoxic potential, they play a crucial role in the central nervous system (CNS). Excessive microglial activation induces inflammation-mediated neuronal damage and degeneration. At present, numerous herbal compounds are able to suppress neurotoxicity via inhibiting microglial activation. Therefore, many researchers focus on pharmacological inhibitors of microglial activation to ameliorate neurodegenerative disorders. Further work should concentrate on the exploration of new herbal compounds, which characteristically inhibit microglial neurotoxicity, rather than modulating neuroprotection alone. In this review, we summarize these herbal compounds, which in the past several years have been shown to exert potential neuroprotective activity by inhibiting microglial activation. The therapeutic targets and pharmacological mechanisms of these compounds have also been discussed.

show abstract

“…1,2 Although spirocyclic systems are unusual scaffolds for bioactive molecules, recent progress on the isolation and characterization of new compounds from natural products and new synthetic routes to spiro building blocks have facilitated their incorporation into more molecules with pharmacological applications, such as antidiabetic, anticancer, anti-Alzheimer's, and in some cases, they have been successfully developed as commercial drugs. [2][3][4][5][6][7][8] It has also been found that an important number of spiro compounds act as antioxidants (AO), substances that may prevent damage caused by reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS are generated in living cells, either naturally or due to some biological dysfunction such as stress.…”

Section: Introductionmentioning

confidence: 99%

Spirocyclic derivatives as antioxidants: a review

et al. 2021

View full text Add to dashboard Cite

show abstract

Synthesis of novel spiro[pyrazolo[4,3- d ]pyrimidinones and spiro[benzo[4,5]thieno[2,3- d ]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

Cited by 28 publications

References 17 publications

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

Sirtuin 1 Inhibiting Thiocyanates (S1th)—A New Class of Isotype Selective Inhibitors of NAD+ Dependent Lysine Deacetylases

Herbal Compounds Play a Role in Neuroprotection through the Inhibition of Microglial Activation

Spirocyclic derivatives as antioxidants: a review

Contact Info

Product

Resources

About