Antitumor activity 30:

The first report dealing with antitumor activity of Rabdosia constituents referred to crude crystalline material isolated from R. trichocarpa (132, 137-139). Subsequently, enmein (62) and enmein diacetate (195) were shown to have antitumor activity against Ehrlich ascites carcinoma, while dihydroenmein (81) was inactive (133). Although at the time the structure of enmein (62) had not been established it was assumed that the cx-methy-lenecyclopentanone whose presence had been recognized was essential for activity (133). 

Various acylated oridonins have also been examined 141). An increase in the chain length of 14-acyloridonins tended to increase antitumor activity thus the activities of 14-dodecanoyl-, tetradecanoyl-, and hexade-canoyl oridonin were higher than that of oridonin itself. On the other hand, acylation of the 6-OH group resulted in deactivation, an observation which supported the important role of this hydroxyl in hydrogen-bonding to the C-15 carbonyl mentioned earlier 141). 

Acylation of enmein (62) led to an increase in antitumor activity, but also to an increase in toxicity the 6-propanoate, benzoate, and hexade-canoate had increased activity 130). 

The antitumor activity of spirolactone-type diterpenoids has also been studied. Shikodonin (88) had antitumor activity 64). Very recently in vivo antitumor activity has been reported for trichorabdals A-C (92-94) and related diterpenoids against Ehrlich ascites carcinoma in the mouse. The trichorabdals exhibited greater activity than oridonin and while the activity of their dihydro derivatives was greatly reduced, they were still active, in contrast to dihydroenmein and its analogs which are inactive. Hence, the trichorabdals may possess a second active site, presumably the spirolactone aldehyde part, and it was assumed that the enhanced activity of the trichorabdals is due to synergism between the two active sites 82, 142). 

Relatively weak antitumor activity is present in the c -8,9-secokaurene-type diterpenoids (101), (103), and (104) but not in 0-methylshikoccin (102). The oxidation product (211) of shikoccin exhibited greatly increased activity compared with that of shikoccin (101), a result also attributed to a synergistic effect of the plural active centers 82). 

5-Nitrotetrahydro-l,3-oxazine derivatives show cytotoxic activity in vitro,2 3 2M and antitumor properties against subcutaneous tumors in mice.84,286 Compound 124 reduced tumors by 70%. The preparation of these compounds is covered by patents.41-46 

3-Oxazines without a nitro group have also been suggested as antitumor compounds.56 Maytansinoids possess antileukemic and antitumor activity275-279-286 with the exception of Maytansinol.279 

Bis(thiosemicarbazones) [89-97] and AT-heterocyclic thiosemicarbazones comprise two interesting series of experimental chemotherapeutic agents. 2-formylpyridine thiosemicarbazone, the first of the latter series to be examined for biological activity, showed mild antileukemic activity against 1-1210 tumor in mice [98]. However, it was found to be toxic at the therapeutic dose levels which led to synthesis of other aromatic and heterocyclic thiosemicarbazones as potential agents [80, 99, 100]. However, the only active anticancer compounds besides glyoxal bis(thiosemicarbazones) were the iV-heterocyclic thiosemicarbazones [101], 2 formyl-3-hydroxypyridine thiosemicarbazone [102] and 

The results of the Ames test for mutagenesis Indicate that many ruthenium compounds Introduce serious lesions into cellular genetic material so that an error-prone DNA repair mechanism is Induced. These results are similar to those obtained for clsplatln (M) and suggest that these complexes probably bind directly to nuclear DNA. In concert with this, many of the ruthenium complexes also Inhibit cellular DNA synthesis (H, ), another property also noted for the cls-platlnum drugs. Unfortunately, however, there Is no correlation between either of these studies and the antitumor activity of ruthenium compounds tested In animal systems. 

A high percentage of the compounds tested, which would be expected to function as Ru(III)-prodrugs, have exhibited antitumor activity In rats. An exception to this are those complexes containing blpyrldyl or o-phenanthrollne ligands which strongly stabilize the lower valent state and which 

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

Compound Time (Hrs) Tumor Blood Muscle (Tumor/Tissue Ratios in Liver Kidney Parentheses) TCI 

Pycnogenols are a heterogeneous group of flavonoids from French maritime pine bark. The name pycnogenols is a term which was given for the designation of flavan-3-ol derivatives by Masquelier et al. [70] 

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Anti thymocyte globulin Antitrypsin Anti tuberculin agents Antitumor activity... 

Plants and microorganisms produce unique and diverse chemical stmctures, some of which act as immunomodulators (18—28). Of specimens used in traditional medicine, approximately 450 plant species have shown antiviral activity out of 4000 plants screened (19). Several tannins (20) exhibit strong inhibition of tumor promotion experimentally. Pretreatment of mice with small amounts of tannins for several days strongly rejected transplanted tumors. This activity has been claimed to be effected through enhancement of host-mediated antitumor activity. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Biomedical Uses. The molybdate ion is added to total parenteral nutrition protocols and appears to alleviate toxicity of some of the amino acid components in these preparations (see Mineral NUTRIENTS) (97). Molybdenum supplements have been shown to reduce iiitrosarnine-induced mammary carcinomas in rats (50). A number of studies have shown that certain heteropolymolybdates (98) and organometaUic molybdenum compounds (99) have antiviral, including anti-AIDS, and antitumor activity (see Antiviral agents Chemotherapeutics, anticancer). 

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). 

Miscellaneous. Reductioa of a palladium salt by CO is the basis of a visual test for ambieat carboa moaoxide (227). Palladium compouads are used as photographic seasitizers (228). The low dimensional mixed valeace compouad Csq g3[Pd(S2C2(CN)2)] 0.5H2O behaves as a semimetal at room temperature (229). Palladium compouads isostmctural with poteat platiaum antitumor compounds have poor antitumor activity (230). 

The trienomycins ate isolated from Streptomjces sp. 83-16 (43,44). The assigned stmctures (Fig. 12) were based on spectral data. Acid hydrolysis of trienomycin A yielded D-alanine (42,44). The trienomycins have no antimicrobial activity but have good antitumor activity. Trienomycin A is the most active, exhibiting good in vivo antitumor activity against sarcoma 180 and P 388 leukemia in mice (241). 

Several semisynthetic maytansinoids have been prepared by acylating the C-3 hydroxyl group of maytansinol. Some of these derivatives have antiprotozoal and antitumor activity similat to maytansine (104) and ansamitocin P-3 (127) (52,254). 3-Epimaytansinoids have been synthesized and were not biologically active (255). 

Biological Activity. The maytansinoids possess antitumor activity, particulady against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity (52,255). The maytansides lack antitumor activity, indicating that the ester at C-3 is a requirement for activity (50,52). The carbinolamide also appears to be necessary for... 

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

Steroid Antibiotics. The steroid antibiotics are a stmcturaHy diverse class of steroids that have a common biological function, ie, antibacterial, antifungal, antiviral, or antitumor activities. This group of compounds can overlap with other steroid classes Hsted above. Eusidic acid [6990-06-3] (67), helvohc acid [29400-42-8] (68), and cephalosporin [13258-72-5] (69) exemplify a set of antibacterial steroids that contain a prolanostane skeleton with an... 

I. H. Goldberg, in C. Chagas and B. Pullman, eds.. Molecular Mechanisms of Carcinogenic and Antitumor Activity, The Vatican Press distributed by Adenine Press, Guildedand, N.Y., 1987, p. 425. 

Salts of neodecanoic acid have been used in the preparation of supported catalysts, such as silver neodecanoate for the preparation of ethylene oxide catalysts (119), and the nickel soap in the preparation of a hydrogenation catalyst (120). Metal neodecanoates, such as magnesium, lead, calcium, and zinc, are used to improve the adherence of plasticized poly(vinyl butyral) sheet to safety glass in car windshields (121). Platinum complexes using neodecanoic acid have been studied for antitumor activity (122). Neodecanoic acid and its esters are used in cosmetics as emoUients, emulsifiers, and solubilizers (77,123,124). Zinc or copper salts of neoacids are used as preservatives for wood (125). 

The novel agent sulofenur (69) has entered clinical trials based on its broad spectmm antitumor activity in tumor models, its unusual mechanism of action, and its lack of cross-resistance to other agents (33). In Phase I clinical trials, the dmg was well tolerated and some clinical responses were noted. 

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Enzymes Degrading Macromolecules. Enzymes that degrade macromolecules such as membrane polysaccharides, stmctural and functional proteins, or nucleic acids, have all shown oncolytic activity. Treatment strategies include the treatment of inoperable tumors with pepsin (1) antitumor activity of carboxypeptidase (44) cytotoxicity of ribonudease (45—47) oncolytic activity of neuraminidase (48—52) therapy with neuraminidase of patients with acute myeloid leukemia (53) antitumor activity of proteases (54) and hyaluronidase treatment in the management of human soHd tumors (55). 

Protease has also been demonstrated to exhibit antitumor activity. Intratumoral microinjection of proteases from Serratia marcescens into mice with sohd tumors resulted in necrosis and solubilization of the tumor mass (53). 

The antitumor activity displayed by the mitosanes and many synthetic aziridines stems from their ability to act as alkylating agents which chemically modify (crosslink) DNA. For this reason, a large number have been screened for antitumor activity, the mechanism of which has been the subject of considerable research effort <75CJC289l). An excellent account of the broad spectrum of biological properties of a multitude of compounds containing the aziridinyl moiety has been published [Pg.93]

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

Oligosaccharides also occur widely as components (via glycosidic bonds) of antibiotics derived from various sources. Figure 7.20 shows the structures of a few representative carbohydrate-containing antibiotics. Some of these antibiotics also show antitumor activity. One of the most important of this type is bleomycin A2, which is used clinically against certain tumors. 

Indeed, the observation that vanadate is a potent inhibiter of phosphate-recognizing enzyme systems was a great stimulus to work in this area, but it now seems likely that its action is more complicated than simple mimicry of phosphates.This is germane to obtaining an understanding of the antitumor activity of [V( j -C5H5)2Cl2]. 

In this fashion, an a-ketoester was utilized as a means of studying the antiviral and antitumor activity of thiophene derivatives of pyrazofurin 14." Reactions between dimethylthiodiglycolate and 15 provided intermediate 16, which was elaborated to 17 and 18 for comparisons with the antitumor activity of the C-nucleoside pyrazofurin 14. 

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