Compound anticancer activity

The Sonogashira reaction provides an important way to make the ene-diyne antibiotics. Symmetrical ene-diynes may be synthesized in one step from two moiecuiesofa terminai aikyne and Z-dihaloethylene. The ene-diyne part of the molecule does the remarkable Bergmann cyclization to give a benzene diradical the ene-diyne is able to penetrate DNA and the diradical is able to react with it, giving the compounds anticancer activity. To make the most biologically active compounds, however, the reaction is performed sequentially, allowing different functionality on each of the aikyne units. 

Many other bisben2ylisoquinoliae alkaloids, such as tetrandriae (80), from Cjcleapeltata Hook., are also known. Compound (80), for example, although it causes hypotension and hepatotoxicity ia mammals, ia other tests, possessed enough anticancer activity to be considered for preclioical evaluation (55). The arrow poison tubocurare prepared from Chondrendendron spp. also contains the bisben2yhsoquiQoline alkaloid tubocurariae (9). 

Antineoplastic Drugs. Cyclophosphamide (193) produces antineoplastic effects (see Chemotherapeutics, anticancer) via biochemical conversion to a highly reactive phosphoramide mustard (194) it is chiral owing to the tetrahedral phosphoms atom. The therapeutic index of the (3)-(-)-cyclophosphamide [50-18-0] (193) is twice that of the (+)-enantiomer due to increased antitumor activity the enantiomers are equally toxic (139). The effectiveness of the DNA intercalator dmgs adriamycin [57-22-7] (195) and daunomycin [20830-81-3] (196) is affected by changes in stereochemistry within the aglycon portions of these compounds. Inversion of the carbohydrate C-1 stereocenter provides compounds without activity. The carbohydrate C-4 epimer of adriamycin, epimbicin [56420-45-2] is as potent as its parent molecule, but is significandy less toxic (139). 

For example, treatment of dione 12 with hydrochloric acid yielded furan 13, a key synthetic intermediate for the production of a variety of compounds that were recently investigated for anticancer activity. Related inquiries by members of the same research team identified furans derived from IS as potential treatments for RNA viruses. Furan IS was prepared by condensation of dione 14 with catalytic sulfuric acid in refluxing acetic anhydride. ... 

This survey of the literature data on the interactions of organotin(IV) cations with biologically active ligands demonstrates that this is still a very open field. Above all, it is necessary to emphasize that usage of such complexes to treat humans is not permitted at present. Consequently, all compounds examined and discussed here (although with promising anticancer activity) are in the exploratory research stage. 

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

As 2-amino-2-deoxy-D-mannose is tumorstatic and 2-acetamido-2-deoxy-D-mannose 6-phosphate is an obligatory intermediate in the biosynthetic pathway to sialic acid, displacement of the essential OH-6 with a fluorine atom should be interesting from the biological viewpoint. 2-Acetamido-1,3,4-tri-0-acetyl-2,6-dideoxy-6-fluoro-D-mannopyranose (see Table 111 in Section 11,3) and its O- and A,0-deacetyl derivatives were prepared the first compound showed weak anticancer activity. 

Entries 4 and 5 are examples of use of the Sakurai reaction to couple major fragments in multistage synthesis. In Entry 4 an unusual catalyst, a chiral acyloxyboronate (see p. 126) was used to effect an enantioselective coupling. (See p. 847 for another application of this catalyst.) Entry 5 was used in the construction of amphidinolide P, a compound with anticancer activity. 

Most of the l,2,4-triazino-l,2,4,5-tetrazine derivatives 4 have been evaluated in vitro for antitumor activity. Results showed that these compounds exhibited a moderate anticancer activity toward leukemia <2003PS2055>. For biological activities of the previous compounds discussed in CHEC-II(1996), please refer to the same <1996CHEC-II(8)743>. 

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

Fig. 11. Molecular structures of (a) fac-[RuCl3(NH3)3], the first reported ruthenium complex with anticancer activity, and (b) NAMI-A and KP1019, two ruthenium compounds currently in clinical trials.

Since the discovery of the high anticancer activity of taxol, much attention has been drawn to its asymmetric synthesis. The total synthesis stood for more than 20 years as a challenge for organic chemists. The compound taxoids are diterpenoids isolated from Taxus species and have a highly oxidized tricyclic carbon framework consisting of a central eight-membered and two peripheral six-membered rings (see Fig. 7-2).21... 

The large diversity of biological activities including antimalarial, antioxoplasmosis, antileishmaniasis, antishistosomiasis, antitrypanosomiasis, antiviral, antifugal and even anticancer activities displayed by artemisinin and artemisinin derivatives (cf. Ref. 55 for a review) added to the multitude of artemisinin-inspired trioxanes, trioxolanes, tetraoxa-cycloalkanes and peroxide, homodimeric-, trimeric- and even tetrameric artemisinin derivatives recently designed and synthesized is a clear indication that in the future, these compounds will become even more important in the chemotherapy of various diseases, perhaps even above and beyond those mentioned here. 

One of the major difficulties in the synthesis of these binary indole-indoline alkaloids is the necessity of generating the natural PARF (priority antireflective) (12) relative stereochemistry between C-14 and C-16, as well as the requirement for controlling the absolute stereochemistry at C-16, which must be (5). Other epimers at these positions lack the high cytotoxicity, with mitotic arrest at metaphase, that is the basis of the anticancer activity of these compounds (13,14). 

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