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Top scoring binding pose of the most active substituted THIQ (2b) at the active site of ERβ-RAL complex (1QKN).
Source publication
Breast cancer is a leading cause of mortality among women, resulting in more than half a million deaths worldwide every year. Although chemotherapeutic drugs remain the main stay of cancer treatment, it is observed that toxicity to normal cells poses a limitation to their therapeutic values. Moreover, the patient recovery rate from advanced breast...
Citations
... Further active THIQ-based compounds from the Redda group demonstrated that phenolic groups on the THIQ skeleton, such as compounds 7 and 8 in Figure 3, resulted in some of the most active compounds. 13,14 However, what caught our attention was the fact that so few of the THIQ compounds prepared by Redda and co-workers had the phenolic OH group in the 6-position, as was demonstrated to be rather important by Chesworth and colleagues. 11 The importance of this phenolic group was also illustrated by our collaboration with the Brunsveld group, where it was demonstrated that the 6-OH group on compound 9 had a significant impact (up to 4 × lower EC 50 ) on the ERα and ERβ EC 50 activity of the compounds (Figure 4, a). ...
... 8 In terms of a direct connection between THIQs and SERM-based breast cancer therapy, pharmaceutical companies were quick to pick up on this important association. In a series of studies, researchers from Novartis 9,10 and Pfizer 11 Further inspection of the molecules synthesized and tested by Redda [12][13][14][15] indicated that firstly, most possess large aryl groups connected via hydrazine-themed linker groups to the nitrogen atom of the THIQ motif. Secondly, the aryl groups attached to the nitrogen atom were limited in terms of their number, type and position of functional groups on the aryl group (see earlier work regarding a series of tetrahydroisoquinoline-N-phenylamide derivatives by Lin and co-workers 27 ). ...
... Investigations by Redda, [12][13][14][15] together with our own unpublished docking studies, indicated a measure of uncertainty as to how THIQ analogues containing an N-aryl linker group would behave within the binding pocket of the ER protein (it should also be noted that we were willing to expand this paradigm to include the question as to whether the motifs were in fact targeting tubulin, rather than the ER). To extend our investigation into this area, a further library of THIQ analogues containing differently substituted aryl groups on nitrogen were designed and synthesized in order to discover whether any activity could be significantly associated with this group. ...
Aim:
The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis and anti-cancer agents.
Background:
Cancer is the second leading cause of deaths in United States. The current recovery rate from the advanced treatment for the cancer is unacceptably low. Therefore, identification of novel, potent and less toxic anticancer agents remains a top priority.
Objective
To 1) evaluate anti-angiogenesis, anticancer activities of THIQs on different colorectal cancer cell lines (CRC) viz., Colo320, DLD-1, HCT116, SNU-C1, SW480 and GSK3b in pre-treated viability HCT116. 2) Undertake molecular docking studies of THIQs.
Methods
Twenty synthesized THIQs were screened in the Eli Lilly’s Open Innovation Drug Discovery Program and selected twelve compounds for in vitro primary screening in the KRas (Kirsten rat sarcoma)-Wnt SL (Synthetic Lethal) in the basal viability of different colon cancer cell lines. Docking studies of the active THIQs were also performed in our laboratory, targeting the active sites of KRas and VEGF receptors.
Results
Compound GM-3-18 was found to possess significant activities for KRas inhibition, with IC50 values in the rage of 0.9 µM to 10.7 µM, for all colon cancer cell lines. Compound GM-3-121 showed potent anti-angiogenesis activity with IC50 = 1.72 µM. Molecular docking studies showed that the carbonyl oxygen atoms of GM-3-18 and GM-3-121 showed hydrogen bonding interactions with the hydrogen of - OH groups of THR 74 (A).
Conclusion
The results indicated that all the compounds showed moderate to high activity for KRas inhibition. The THIQs bearing the chloro group at the 4-postiton of the phenyl ring (GM-3-18) exhibited significant KRas inhibition against all colon cancer cell lines.
Background:
Cancer is at present one of the leading causes of death in the world. It accounts for 13% of deaths occurred worldwide and is continuously rising, with an estimated million of deaths up to 2030. Due to poor availability of prevention, diagnosis and treatment of breast cancer, the rate of mortality is at alarming level globally. In women, hormone-dependent estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers. Hence, it has drawn the extensive attention of researchers towards the development of effective drugs for the treatment of hormone-dependent breast cancer. Estrogen, a female sex hormone has a vital role in the initiation and progression of breast malignancy. Therefore, estrogen receptor is the central target for the treatment of breast cancer.
Conclusion:
In this review, we have studied various classes of antiestrogens that have been designed and synthesized with selective binding for estrogen alpha receptor (ER). Since estrogen receptor α is mainly responsible for the breast cancer initiation and progression, therefore there is need of promising strategies for the design and synthesis of new therapeutic ligands which selectively bind to estrogen alpha receptor and inhibit estrogen dependent proliferative activity.
