NCI assay

The problem with the ether and ester linkage is that they are often hydrolytically unstable, and so there have been approaches to replace the CIO acetal linkage with more chemically robust linkages. Posner s group prepared a series of CIO olefinic non-acetal dimers and CIO saturated dimers that showed good antiproliferative activities . Dimers 108-110 were aU especially potent and selective at inhibiting leukaemia and colon cancer in the NCI assay (Scheme 38) . ... 

Fluorescent dyes such as calcein-AM and rhodamine derivatives have been demonstrated to be P-gp substrates (400-407). These compounds can be used in any competition assay in which the test compound is added with these dyes. Any reduction in the dye efflux would be indicative of the inhibitory properties of the test compounds toward P-gp. Both rhodamine 123 and calcein-AM have been used in high-throughput assays, including the NCI assay, to screen large numbers of compounds as inhibitors of P-gp in several cell types. Calcein-AM itself is a weakly fluorescent molecule. When the acetoxymethyl ester group is cleaved by... 

Compounds 44, 51, and 52-56 were evaluated for their antitumor activity according to NCI in vitro protocols [23]. They were assayed in vitro against three cancer types breast, lung, and central nervous system (CNS) cancers. 

We use assay data from a National Cancer Institute HIV/AIDS database in our study (http //dtp,nci,nih.gov/docs/aids/aids data.html). As descriptors, we apply a set of six BCUT descriptors and a set of 46 constitutional descriptors computed by the Dragon software. These descriptors could be computed for 29,374 of the compounds in the database. The assay classifies each compound as confirmed inactive (Cl), moderately active (CM), or confirmed active (CA). We treat the data as a binary classification problem with two classes inactive (Cl) and active (CM or CA). According to this classification, 542 (about 1.8%) of the compounds are active. 

Current efforts favor tumor cell line tests, conducted by the National Cancer Institute (NCI) drug development program [62]. In the current NCI anticancer screen, each compound is tested against 60 human tumor cell lines derived from several cancer types (lung, colon, melanoma, kidney, breast, ovary, brain, leukemia). The tumor cells are seeded on 96-well microtiter plates and pre-incubated for 24 h. The test agents are then added to the wells (five 10-fold dilutions 0.01 -100 pmol/1) and are incubated for 48 h with the tumor cell lines. At the termination of the assay, the cells are fixed in situ with trichloroacetic acid (TCA), washed and dried. Sulforhodamine B (SRB), a dye that binds to the basic amino... 

Posner and coworkers have prepared a series of semi-synthetic and synthetic ether and ester-linked dimers that were found to have potent anti-proliferative and antitumour activities in vitro. Some of these trioxane dimers were found to be as antiproliferative as calcitriol, the hormonally active form of vitamin D, which is used to treat psoriasis, a skin disorder characterized by uncontrolled cell prohferation. Of the semi synthetic dimers, a polyethylene glycol-linked dimer 107, with S-stereochemistry at both of the lactol acetal positions, was found to be very anti-proliferative and showed activity against leukaemia and colon cancer cell hues in the National Cancer Institute (NCI), USA 60-cell line assay. 

O Neill and coworkers have also sought to address the problem of the metabolically susceptible CIO acetal linkage . A series of CIO carba dimers were prepared and assayed for antitumour activity. The two most potent compounds that were prepared are two phosphate ester finked dimers 115 and 116 (Scheme 40). They are principally active against leukaemia, colon and certain melanoma and breast cancer cell lines in the NCI 60-cell line assay. 

The tools have recently been compared and evaluated in the context of molecule mining.1111 Worlein el al. reimplemented all four methods (same code base, programming expertise and optimization effort). Benchmarks were carried out on a comprehensive set of graph databases, including molecular databases. The molecular databases used were the IC93 (1283 compounds),1121 the HIV assays 1999 (42 689 compounds)1131 and the NCI (237 771 compounds).1141... 

HIV assay, dtp.nci.nih.gov/docs/aids/aids data.html. 

QDO 59 antitumoral in vitro assays against MCF7 (breast), NCI-H460 (lung), SF-268 (CNS) and leukemia cells [152]... 

The top-scoring 2,000 compounds were then clustered based on structural similarity, and the representatives of the top-ranking 12 clusters along with compound S5 of Amaro et al. (31) were tested experimentally using a fluorescence-based RNA-editing assay (49). Interestingly, the assays proved compounds S5 and C35—which is the same as compound V2 in Durrant et al. (47) (see Note 19)—as well as two other NCI compounds to be inhibitors. 

All assays contained 1 mM MnCl2 and 4.5 nCi of UDP-[14C]xylose, phis sufficient unlabeled UDP-xylose and UDP-glucose to give the concentrations indicated. 

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