Synthesis and In Vitro Evaluation of Novel 1,2,3,4-Tetrahydroisoquinoline Derivatives as Potent Antiglioma Agents

Patil, Renukadevi; Hosni-Ahmed, Amira; Jones, Terreia S.; Patil, Shivaputra A.; Asres, Likeselam B.; Wang, XiangDi; Yates, Ryan; Geisert, Eldon E.; Miller, Duane D.

doi:10.2174/18715206113139990328

Cited by 6 publications

(8 citation statements)

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“…EDL-360 was prepared as previously described [ 5 ]. For in vitro screening, a freshly prepared 50 μM stock solution was prepared by dissolving EDL-360 in DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, there is an urgent need to find new therapeutic approaches to improve patient survival and outcome. We previously showed that tetrahydroisoquinoline (THIQ) derivatives possessed potent antiglioma activity [ 5 ]. Structure activity relationship studies showed that EDL-360 is the most potent THIQ derivative against glioma cell cultures.…”

Section: Introductionmentioning

confidence: 99%

“…Structure activity relationship studies showed that EDL-360 is the most potent THIQ derivative against glioma cell cultures. The IC 50 values ranged from approximately 5–10 μM in multiple cancer cell lines [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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EDL-360: A Potential Novel Antiglioma Agent

Hosni-Ahmed¹,

Sims

Jones

et al. 2014

J Cancer Sci Ther

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Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for more than 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains dismal. The main focus of our research is to identify potent novel antiglioma small molecules. We previously showed that EDL-360, a tetrahydroisoquinoline (THIQ) analog, as being highly cytotoxic to human glioma cell cultures. Here we show that EDL-360 significantly induced apoptosis in human glioma cell lines (U87 and LN18). However, in normal astrocytic cells, EDL-360 induced a modest G0/G1 cell cycle arrest but did not induce apoptosis. In an attempt to enhance EDL-360 induced cell death, we tested simultaneous treatment with EDL-360 and embelin (an inhibitor of the anti-apoptotic protein, XIAP). We found that, glioma cells had significant lower viability when EDL-360 and embelin were used in combination when compared to EDL-360 alone. We also used combination treatment of EDL-360 with decylubiquinone (dUb), a caspase-9 inhibitor, and found that the combination treatment induced a significant cell death when compared to treatment with EDL-360 alone. This is the first report that suggests that dUb has anticancer activity, and perhaps acts as a XIAP inhibitor. Finally, our in vivo data showed that EDL-360 treatment induced a partial regression in glioma tumorigenesis and induced cell death in the treated tumors as shown by H&E staining. Taken together these data suggests that EDL-360 has a potential therapeutic application for treating glioma, especially when combined with XIAP inhibitors.

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“…EDL-360 was prepared as previously described [ 5 ]. For in vitro screening, a freshly prepared 50 μM stock solution was prepared by dissolving EDL-360 in DMSO.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EDL-360: A Potential Novel Antiglioma Agent

Hosni-Ahmed¹,

Sims

Jones

et al. 2014

J Cancer Sci Ther

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“…Heliamine is found in some Mexican cacti (Backebergia militaris, Carnegiea gigantea, Pachycereus pecten-aboriginum, Pachycereus pringlei, Pachycereus weberi) (Strombö m & Bruhn, 1978a,b;Mata & McLaughlin, 1980;Pummangura et al, 1982;Menachery et al, 1986) and exhibits strong anticancer action as an inhibitor of rat sarcoma (Strombö m & Bruhn, 1978a,b). Some derivatives of tetrahydroisoquinoline possess anticancer (Patil et al, 2014), antidiabetic (Song et al, 2014), antidepressant (Możdżeń et al, 2014;Antkiewicz-Michaluk et al, 2014a,b;Wąsik et al, 2014) and anticonvulsant (Gitto et al, 2010) action and also have contractile activity against guinea pig's gastric smooth muscle preparations (Ivanov et al, 2011). In addition, heliamines substituted by hydroxyl or carboxyl groups were shown to be low-molecular-weight hydrogelators (Kang et al, 2011(Kang et al, , 2014Xu et al, 2012) which are useful in catalytical and biological applications (Tian et al, 2014;Dö ring et al, 2013;Xu, 2009;Estroff & Hamilton, 2004).…”

Section: Introductionmentioning

confidence: 99%

The formation of the salt and neutral molecule cocrystal from equimolar solution of heliamine and bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid

Shishkina

Isaiev

Urzhuntseva

et al. 2019

Acta Crystallogr Sect B

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The possible interaction of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (heliamine) with bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid anhydride has been studied. Instead of the reaction with heliamine, the acid anhydride was hydrolyzed into the appropriate dicarboxylic acid. An equimolar mixture of unreacted heliamine and in-situ-generated dicarboxylic acid crystallized in space group P2 1 /c. The comprehensive study of the obtained crystals shows that the peculiarities of the crystallization process lead to the formation of the saltcocrystal structure where the dianion interacts simultaneously with two cations forming a chain as the primary structural motif. The neutral molecules of dicarboxylic acid link the dianions of the neighbouring chains, forming a layer as the secondary structural motif. As a result, the stronger hydrogen bonds formed by the neutral molecules play a secondary role in the crystal structure formation.

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“…The IC 50 values ranged from approximately 3-10 μM, depending on the cancer cell line. Therefore, we were interested in investigating the anti-cancer activity of other THIQ analogs in a panel of human glioma cell lines [166].…”

Section: Tetrahydroisoquinoline Derivativesmentioning

confidence: 99%

Glioma: A Tale of Corticosteroids, Thiopurines and Proposed Novel AntiGlioma Small Molecules

Ahmed¹

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Synthesis and In Vitro Evaluation of Novel 1,2,3,4-Tetrahydroisoquinoline Derivatives as Potent Antiglioma Agents

Cited by 6 publications

References 0 publications

EDL-360: A Potential Novel Antiglioma Agent

EDL-360: A Potential Novel Antiglioma Agent

The formation of the salt and neutral molecule cocrystal from equimolar solution of heliamine and bicyclo[2.2.1]hept-5-ene-endo-2,3-dicarboxylic acid

Glioma: A Tale of Corticosteroids, Thiopurines and Proposed Novel AntiGlioma Small Molecules

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