Antileukemic activity

As to the mode of action of these compounds, Liao etal. 54), using HeLa cells, have shown that the antitumor activity of bruceolide (48) esters at the molecular level is due to irreversible inhibition of protein synthesis. The antileukemic activity of a series of esters of brusatol (55 a), bis-brusatol (55b) and bruceantin (53) has been correlated with the ability of these compounds to suppress DNA and protein synthesis in P-388 lymphocytic leukemia cells. The active compounds were also shown to inhibit DNA polymerase activity and purine synthesis (27). 

Studies 47, 108) of the structure/activity relationships for several quassinoids have established some of the structural requirements for optimal antineoplastic activity, particularly in P-388 mouse leukemia. These requirements are principally the following (Chart 2) a) Ring A with 

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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. 

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... 

Antileukemic activity. Aucubin, in combination with caffeic acid, chlorogenic acid, ferulic acid, p-coumaric acid, and vanillic acid, exhibited weak antileukemic activity (inhibitory concentration [ICJjo 26-56 pg/ mL, international system of units 2-11) on human leukemia and lymphoma cell lines. Water-insoluble compounds, such as triterpenoids (oleanolic acid and ursolic acid), monotepene (linalool), and flavonoid (luteolin) produced strong activity " . Anti-nematodal activity. Water extract of the dried seed, at various concentrations, was active on Meloidogyne incognita Anti-yeast activity. Ethanol (80%) extract of the dried entire plant, on agar plate at a concentration of 1 mg/mL, was inactive on Candida albicans K... 

Cycloalkylation (7, 148).2 Cycloalkylation of 2 with (Z)-l was used as one step in a total synthesis of (+ )-sesbanine (6), a constituent of Seshania drummondii seeds with antileukemic activity. The hydroxyl group was introduced into the cyclopentene ring of 4 by iodolactonization followed by reduction to give 5. Final steps included aminolysis of the lactone ring, intramolecular addition of the amide anion to the CN group, and hydrolysis to give 6. 

Many naturally occurring substituted anthraquinones [including morindaparvin-A (60) and -B (61)] and naphthoquinones (including psychorubin and related compounds) possess cytotoxic antileukemic activities.55-57 In the former compounds, removing the hydroxy substituents retained or increased cytotoxicity for example, 62 lacks one hydroxyl (R4 = H) found in 61 (R4 = OH), and is more active in the KB cell line (ID50 61, 4.0 mg/kg 62, 0.09 mg/kg). 

The demonstration that 3-alkoxypyridines are metalated in the 2-position (Scheme 91) (82S235) allowed the preparation of a series of ribo-furanosyl pyridines 565 as potential deazapyrimidine nucleosides for evaluation as thymidylate synthetase inhibitors (Scheme 170) (86MI2). Thus, metalation of the 3-alkoxypyridines 291 followed by condesation at lower temperatures with a protected D-ribose aldehyde afforded diaster-eoisomeric mixtures of compounds 564 which, upon mesylation and acid-catalyzed cyclization, delivered the ribofuranosyl pyridines 565 in high yields. Purification by affinity chromatography afforded the a- and /3-anomers, which showed insignificant antileukemic activity. 

Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against LI 210 and P388 leukemias in mice (89,100, 108), and so some attention has been devoted to the synthesis of the dicar-boxylic acid side chains (see also Section IV,A). 

Decitabine (1) is a hypomethylating agent that exhibits potent antileukemic activity by inducing epigenetic changes in chromatin or reactivating tumor suppressor genes. It is administered intravenously at 15 mg/m2 over 3 h every 8 h for 3 consecutive days. The frequency of this administration is every 6 weeks. 

Gibaud S, Alfonsi R, Mutzenhardt P et al (2006) (2-Phenyl-[l, 3, 2] dithiarsolan-4-yl)-methanol derivatives show in vitro antileukemic activity. J Organomet Chem 691 1081-1084... 

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