Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors.

Field Validation of a Development Data Set for Cochliomyia macellaria (Diptera: Calliphoridae): Estimating Insect Age Based on Development Stage.

Insect age estimates can be useful for estimating the postmortem interval when certain assumptions are met. Such estimates are based on species-specific development data that are temperature-dependent and variable, and therefore prone to different degrees of error depending on the combination of data sets, calculations, and assumptions applied in a specific instance. Because of this potential error, validating the methods employed is necessary for determining accuracy and precision of a given technique. For forensic entomology, validation of development data sets is one approach for identifying the uncertainty associated with insect age estimates. Cochliomyia macellaria (Fabricius) is a primary colonizer of remains across the United States and is commonly encountered in forensic investigations. A development study for this species was produced for a central Texas, U.S. population; the variation associated with this data set and the pre-appearance interval were previously explored in an ecological model. The objectives of this study were to determine the accuracy of the development data and the validity of the ecological model when applied to immatures of known age developing under field conditions. Results indicate this data set is an accurate predictor of insect age when using development stage, supporting the validity of the ecological model in central Texas. Age predictions made with all stages present in a sample were more accurate than predictions made with the most developed stage in a sample, and estimates of age when using the prepupal stage were overestimated regardless of prediction method, though thermal requirements for total development were similar.

Forensic Entomology: Evaluating Uncertainty Associated With Postmortem Interval (PMI) Estimates With Ecological Models.

Estimates of insect age can be informative in death investigations and, when certain assumptions are met, can be useful for estimating the postmortem interval (PMI). Currently, the accuracy and precision of PMI estimates is unknown, as error can arise from sources of variation such as measurement error, environmental variation, or genetic variation. Ecological models are an abstract, mathematical representation of an ecological system that can make predictions about the dynamics of the real system. To quantify the variation associated with the pre-appearance interval (PAI), we developed an ecological model that simulates the colonization of vertebrate remains by Cochliomyia macellaria (Fabricius) (Diptera: Calliphoridae), a primary colonizer in the southern United States. The model is based on a development data set derived from a local population and represents the uncertainty in local temperature variability to address PMI estimates at local sites. After a PMI estimate is calculated for each individual, the model calculates the maximum, minimum, and mean PMI, as well as the range and standard deviation for stadia collected. The model framework presented here is one manner by which errors in PMI estimates can be addressed in court when no empirical data are available for the parameter of interest. We show that PAI is a potential important source of error and that an ecological model is one way to evaluate its impact. Such models can be re-parameterized with any development data set, PAI function, temperature regime, assumption of interest, etc., to estimate PMI and quantify uncertainty that arises from specific prediction systems.