Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

Stevens, Kirk L.; Alligood, Krystal J.; Alberti, Jennifer G. Badiang; Caferro, Thomas R.; Chamberlain, Stanley D.; Dickerson, Scott H.; Dickson, Hamilton D.; Emerson, Holly K.; Griffin, Robert J.; Hubbard, Robert D.; Keith, Barry R.; Mullin, Robert J.; Petrov, Kimberly G.; Gerding, Roseanne M.; Reno, Michael J.; Rheault, Tara R.; Rusnak, David W.; Sammond, Douglas M.; Smith, Stephon C.; Uehling, David; Waterson, Alex G.; Wood, Edgar R.

doi:10.1016/j.bmcl.2008.11.023

Cited by 18 publications

(11 citation statements)

References 14 publications

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“…2, 7-Diamino-thiazolo [4,5-d]pyrimidine analogue 21 showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells [71]. The compounds 22, 23, 25 have retained the 4-benzyloxyaniline portion of lapatinib and show potent and selective EGFR/ErbB-2 enzyme inhibition [27,[42][43]. This is a primary trend to develop difunctional agents in EGFR TK inhibitors in the last two years.…”

Section: "The T790m Mutation and Dual Egfr/her2 Inhibitor"mentioning

confidence: 96%

“…The enumeration of "A" [40][41][42][43][44] displays several templates which would be considered as EGFR/HER2 inhibitors and the templates of "B" [21,45] are designed for potent apoptosis inducers; "C" [46][47] refers to a series of bioactive molecules against Tpl2; "D" [48] is the EphB2 inhibitors as potential anticancer agents; "E" [49] is a new template of kinase inhibition; "F" [50] is novel quinazoline derivatives displaying antiplasmodial properties. In the next section, we will present several typical molecules derived from these templates above and discuss the relationships between them and relative targets.…”

Section: "Quinazoline Ring Body"mentioning

confidence: 99%

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Exploration of Chemical Space Based on 4-Anilinoquinazoline

Li¹,

Hou²,

Wang³

et al. 2012

CMC

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Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, Erlotinib, Lapatinib) suggests that 4-anilinoquinazoline scaffold is still worth developing in the future. To date hundreds of this sort of derivatives have been synthesized and show potent anticancer activities. Most of the compounds have been proved to be EGFR/HER2 kinase inhibitors, binding at the hinge region of the ATP site and some lead compounds have been optimized against a number of different kinases, including VEGFR-2, Src, Aurora A/B, Tpl, Clk and PDE10A. Now there is now a rich pipeline of novel anticancer agents based on 4-anilinoquinazoline in early phase clinical trials. This review will highlight the exploration of chemical space of 4-anilinoquinazoline in the past ten years and we hope that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of anilinoquinazoline derivatives will be beneficial to the rational design of new generation of small molecule anticancer drugs.

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Section: "The T790m Mutation and Dual Egfr/her2 Inhibitor"mentioning

confidence: 96%

Section: "Quinazoline Ring Body"mentioning

confidence: 99%

Exploration of Chemical Space Based on 4-Anilinoquinazoline

Li¹,

Hou²,

Wang³

et al. 2012

CMC

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“…These compounds exhibited a dual inhibitory potential toward EGFR and ErbB2 ( Hubbard et al, 2008 ). It was further reported that modifying the carbamate helps in improving the inhibitory activity and enhances the oral bioavailability of the same ( Stevens et al, 2009 ).…”

Section: Fused Pyrimidine Derivativesmentioning

confidence: 99%

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship

et al. 2022

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Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion. From the literature, it shows that pyrimidine is one of the most commonly studied heterocycles for its antiproliferative activity against EGFR inhibition. The authors have collated some interesting results in the heterocycle-fused pyrimidines that have been studied using different cell lines (sensitive and mutational) and in animal models to determine their activity and potency. It is quite clear that the fused systems are highly effective in inhibiting EGFR activity in cancer cells. Therefore, the structure–activity relationship (SAR) comes into play in determining the nature of the heterocycle and the substituents that are responsible for the increased activity and toxicity. Understanding the SAR of heterocycle-fused pyrimidines will help in getting a better overview of the molecules concerning their activity and potency profile as future EGFR inhibitors.

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“…2 . The acetylene group containing derivatives show antimalarial, 25 antitubercular, 25 kinase inhibition, 26 anticancer, 27 and antimicrobial 27 activities. Acetylenic metabolites from nature such as Hydnum repandum , Polyporus biformis , Drosophila subatrata , etc.…”

Section: Introductionmentioning

confidence: 99%