Antileukemic

Antiknock agent Antiknock index Antileishmanial agent Antileukemic activity Antdon... 

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... 

Spiroplatin (99) in animal studies showed excellent antileukemic activity and was less... 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

In the seven-step stereoselective total synthesis of ptilocaulin 44 [21 ], a potent antileukemic and antimicrobial agent isolated [22] from marine sponges, the oxime 36 was treated with NaOCl providing the tricyclic isoxazoline 38 in 89% yield without isolation of the nitrile oxide intermediate 37 (Scheme 5) [23]. Isoxazoline 38 was obtained as a mixture of four diastereomers and their ratio was... 

A similar method was later used by the group of Tomioka [10] for the asymmetric addition of thiazolylhthium 44 to prochiral aldimines (Scheme 10) for the preparation of (S)-Boc-Doe 46, a component of antileukemic marine natural product dolastatin 10. In this case, sparteine 1 was... 

Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971 93 2325-7. 

Figure 8.4 Typical hit structures for the antileukemic pharmacophore shown at the top of the page, with the presence of the pharmacophore in the retrieved molecules shown by dotted lines.

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... 

Acute myelogenous leukemia has been observed in 0.07% of MS patients treated with mitoxantrone.46 This form of acute leukemia appears within 2 to 4 years of initiating mitoxantrone and is generally responsive to standard antileukemic therapy. 

In HSCT, very high doses of chemotherapy with or without total-body radiation (TBI) are given in an attempt to potentiate leukemia cell kill. Hematopoiesis is restored by the infusion of stem cells harvested from an HLA-compatible donor, thereby rescuing the patient from the consequences of total aplasia.13 It is the most effective antileukemic therapy currently available. 

The antileukemic efficacy of an immunotoxin composed of a monoclonal anti-Thy-1 antibody disulfide linked to the ribosome-inactivating protein gelonin. Cancer Immunol. Immunother. 25, 31. 

Taxol , a compound with powerful antileukemic and tumor-inhibiting activity... 

In Grieco s total synthesis of the antileukemic secoeudesmanolides ivangulin (194)67) and eriolanin (197)68), the Baeyer-Villiger oxidation was again found to be indispensable in the conversion of the cyclobutanones (192) and (195) to the y-lactones (193) and (196)respectively 67,68). 

In contrast, an excellent yield was obtained for the reaction between 5-iodoimidazole and propargyl alcohol in the absence of Cul to install the 5-alkynyl derivative [10, 41], The adduct was then deprotected to 5-alkynyl- l-P-D-ribofuranosylimidazole-4-carboxamide 58, an antileukemic agent. It is noteworthy that if the Sonogashira reaction was conducted in the presence of Cul, the yield dropped to 19%. 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

H Fungi - Amanita phalloides and Agaricus phalloides Cyanobacteria -Lyngbya majuscula Phalloidin, phallicidin, and amanitin - toxic peptides Majusculamide D - cytotoxic peptide Microcolin A - peptide with immunosuppressive, antileukemic and protein kinase C inhibitory activity 242... 

Certain organic forms of mercury can elicit specific damage in the main cell body of peripheral neurons. Similar responses are associated with certain natural products called vincristine and vinblastine, both of which have been used as antileukemic medicines. The deadly botulinum toxins, mentioned earlier in this chapter, block transmission of nerve impulses at the synapses of motor neurons. This blockage results in muscular paralysis which, if sufficiently severe, can lead to death, usually because respiration is impaired. The once widely used pesticide, DDT, is an organic chemical that also acts on the nervous system at this site, although it can also mount an attack on areas of the CNS. 

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