Structure-based Synthesis Research Articles

Synthesis and biological evaluation of new series of quinazoline derivatives as EGFR/HER2 dual-target inhibitors

It is generally believed that EGFR/HER2 dual-target inhibitors may overcome the resistance of EGFR TKIs caused by HER2 overexpression. The structure-based synthesis and biological evaluation of quinazoline derivatives as EGFR/HER2 dual-target inhibitors has been studied in this paper. II-1, II-2, III-3, III-4 displayed comparable inhibitory potency against EGFR and HER2 and II-1 showed remarkable antiproliferative activities against NCI-H358/PC-9/Calu-3/NCI-H1781 (EGFR IC50 = 0.30 nM, HER2 IC50 = 6.07 nM, NCI-H358 GI50 = 23.30 nM, PC-9 GI50 = 1.95 nM, Calu-3 GI50 = 23.13 nM NCI-H1781 GI50 = 41.61 nM).

Synthesis and biological evaluation of novel 5,6-dihydrobenzo[h]quinazoline derivatives as FLT3 inhibitors.

Fms-like tyrosine kinase 3 (FLT3) is widely expressed and often mutated in acute myeloid leukemia (AML), which makes it an important target for the treatment of AML. The structure-based synthesis and biological evaluation of 5,6-dihydrobenzo[h]quinazoline derivatives as FLT3 inhibitors have been studied in this paper. III-1a, III-1c, III-2a, III-2c, and III-4a displayed comparable inhibitory potency against FLT3-ITD and showed remarkable antiproliferative activities against MV4-11.

Pyrazolo[1,5-a]pyrimidine based Trk inhibitors: Design, synthesis, biological activity evaluation

Tropomyosin receptor kinases (Trks), a transmembrane receptor tyrosine kinases, have attracted more and more attention as a drug target. Here we reported the structure-based synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors, which exhibited potent Trk inhibitory activities. Particularly, compounds 8a, 8f, 9a, 9b and 9f (IC50 < 5 nM) showed significant inhibitory potency against Trk.

Synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors

As a class III receptor tyrosine kinase (RTK), FMS-like tyrosine kinase 3 (FLT3) is always overexpressed in many cases of acute leukemia. This paper studies the structure-based synthesis and biological evaluation of diaryl urea derivatives as FLT3 inhibitors. Encouragingly, compounds 15b, 16b, 24a, and 24c showed excellent biological activities in a low nanomolar range. In particular, compound 16b demonstrated significant inhibitory potency against FLT3-ITD (IC50 = 5.60 nM) and better antiproliferative activity than quizartinib against MV4-11 cell line (IC50 = 0.176 nM). It is indicated that compound 16b for the treatment of acute myeloid leukemia could be very promising.

Synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as potent CDK2 inhibitors

As serine/threonine kinase, the cyclin dependent kinase 2 (CDK2) is a promising target for various diseases such as cerebral hypoxia, cancer, and neurodegenerative diseases. Here we reported the structure-based synthesis and biological evaluation of novel 5,6-dihydropyrimido[4,5-f]quinazoline derivatives as CDK2 inhibitors, which exhibited potent CDK2 inhibitory activities, as well as anticancer activities in low concentration against two human cancer cell lines (MCF-7 and HCT116). In particular, compounds 11a and 11f (IC50 values of 0.11 and 0.09 μM for CDK2, respectively) have demonstrated significantly inhibitory potency against CDK2 and have showed great inhibitory activities against MCF-7 and HCT116 cell lines.

Structure-based synthesis: From natural products to drug prototypes

AbstractX-ray crystallographic data available from complexes of natural and synthetic molecules with the enzyme thrombin has led to the design and synthesis of truncated and hydrid molecules exhibiting excellent inhibition in vitro. The design element has also been extended to the synthesis and in vitro inhibition of a series of achiral molecules deploying aromatic and heterocyclic core motifs with appropriately functionalized appendages that provide excellent binding interactions at the S1, S2, and S3sites of thrombin. Excellent selectivity for thrombin over trypsin has also been observed. Thus, studies in total synthesis of highly active natural aeruginosins have inspired further work toward truncated and hybrid analogs with excellent inhibitory activities. Structure-based organic synthesis has guided our research from natural products toward unnatural drug-like prototypes.

Interactive example-based urban layout synthesis

We present an interactive system for synthesizing urban layouts by example. Our method simultaneously performs both a structure-based synthesis and an image-based synthesis to generate a complete urban layout with a plausible street network and with aerial-view imagery. Our approach uses the structure and image data of real-world urban areas and a synthesis algorithm to provide several high-level operations to easily and interactively generate complex layouts by example. The user can create new urban layouts by a sequence of operations such as join, expand, and blend without being concerned about low-level structural details. Further, the ability to blend example urban layout fragments provides a powerful way to generate new synthetic content. We demonstrate our system by creating urban layouts using example fragments from several real-world cities, each ranging from hundreds to thousands of city blocks and parcels.

A proof-of-principle pharmacokinetic, pharmacodynamic, and clinical study with purine nucleoside phosphorylase inhibitor immucillin-H (BCX-1777, forodesine)

The discovery of purine nucleoside phosphorylase (PNP) deficiency and T lymphocytopenia suggested that inhibition of this enzyme could serve as a therapeutic target. Inhibitors of PNP failed until structure-based synthesis of immucillin-H (BCX-1777, forodesine), a transition-state analog of PNP. The picomolar potency for PNP, T cell-selective cytotoxicity, and animal studies provided the rationale for use of forodesine in T-cell malignancies. Five patients were treated with an intravenous infusion of forodesine (40 mg/m2) on day 1; treatment continued on day 2; forodesine was administered every 12 hours for an additional 8 doses. Plasma and cellular pharmacokinetics and pharmaco-dynamics were investigated. Median peak level of forodesine (5.4 microM) was achieved at the end of infusion. This level was sufficient to increase plasma 2'-deoxyguanosine (dGuo) concentrations in all patients. Intracellular deoxyguanosine triphosphate (dGTP) increased by 2- to 40-fold in 4 of 5 patients (8 of 9 courses) and correlated with antileukemia activity in 4 patients. However, objective responses were not observed. This was the first clinical study in humans to demonstrate the plasma pharmacokinetics and the pharmacodynamic effectiveness of the PNP inhibitor, forodesine; however, regrowth of leukemia cells in the blood and marrow after course 1 suggested that a different therapeutic schedule should be considered for future studies.