Anticancer program

Figure 8.2 Example of a 2D substructure search. The search is for the diphenyl ether query substructure at the top of the figure, below which are shown five of the hits resulting from a search of the National Cancer Institute database of molecules that have been tested in the US government anticancer program (see URL http //dtp.nci. nih.gov/). This database is also used for the search outputs shown in Figures 8.3 and 8.4.

The synthesis of the leading candidate compound 47 in an anticancer program [79,80] required (S)-2-chloro-l-(3-chlorophenyl)ethanol 48 (Figure 16.13) as an intermediate. Other possible candidate compounds used analogs of the (S)-alcohol. From microbial screening of reduction of ketone 49 to the (S)-alcohol 48, two cultures, namely, Hansenula polymorpha SC13824 (73.8% EE) and Rhodococcus globerulus... 

HiBASAMi H, ACHiwA Y, FUJIKAWA T and KOMIYA T (1996) Induction of programmed cell death (apoptosis) in human lymphoid leukemia cells by catechin compounds . Anticancer Res, 16, 1943-46. 

Perhaps the most exciting story about an anticancer agent derived from a natural product is that of Taxol . That story begins in 1958, when the National Cancer Institute began a program to screen natural products for substances that might have anticancer activity. The... 

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... 

Compounds 436 and 437 have been tested by the National Cancer Institute (NCI) at Bethesda in a disease-oriented in vitro anticancer screening program against 60 human tumor cell lines, showing moderate activity <2004JOC3672>. 

Parallel to our group, a few other researchers also performed significant studies on anticancer (3-lactams. For example, (3-lactam derivatives (Fig. 2) induced DNA damage, inhibited DNA replication, and activated the apoptotic death program in human leukemic Jurkat T cells in a time and concentration-dependent manner. Importantly, (3-lactam 69 also inhibited proliferation and induced apoptosis in other human solid tumor cell lines (breast, prostate, and head-and-neck). It was believed that induction of apoptosis by 69 is associated with activation of p38 mitogen-activated protein (MAP) kinase, release of mitochondrial cytochrome c, and activation of the caspases. It was reported that apoptosis is blocked by a specific inhibitor to p38 kinase, implicating p38 MAP kinase as the major factor in (3-lactam-induced apoptosis [154]. This study was very significant. 

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