Antileukemic activity in vivo

Bioassay-guided fractionation of an alcoholic extract of B. megapotamica, which showed significant activity in vivo against P-388 leukemia in mice and in vitro against cells derived from human carcinoma of the nasopharynx, yielded four potent antileukemic trichothecenes baccharin, Fig. (57), baccharinol, Fig. (58), isobaccharinol, Fig. (59) and isobaccharin, Fig. (60) [84],... 

Eriolanin (104) is a novel antileukemic seco-eudesmane and was isolated by Kupchan and co-workers [45]. It possesses significant activity in vivo against P-388 leukaemia in mice and in vitro against cell cultures derived from human carcinoma of the nasopharynx (KB). Grieco developed an ingenious synthesis[46] of eriolanin (104), which has been depicted in "Fig (9)". 

Several xanthones that possess antidepressant activity inhibit monoamine oxidases. These compounds have in vitro cytotoxicity and in vivo antitumor activity (Hostettmann and Hostettmann, 1989). The xanthone psorospermin (38) from Psorospermum febrifugum (Clusiaceae) exhibited antileukemic activity in several test systems. Other xanthones have tuberculostatic effects (Vermes and Wagner, 1986). 

Chaparrinone (40a) which possesses most of the structural requirements for in vivo antileukemic activity in the PS test system but lacks an ester side chain at C-15 and/or at C-6, does not display any significant antineoplastic activity. In a search for direct methods of quassinoid functionalization benzeneselininic anhydride (84) was considered as a possible reagent for the introduction of a double bond in the lactonic ring of chaparrinone (40 a) (41). 

Other lignans with known antitumor properties are (+)-wikstromol 90 isolated from Wikstroemia foetida var. oahuensis Gray (Thymelaeaceae) (92) and (-)-burseran 91 from Bur sera microphylla (Burseraceae) (93). (-)-Steganacin 92 and (-)-steganangin 93, isolated from Steganotaenia araliacea stem bark and wood, exhibit antileukemic activity in the in vivo murine P-388 lymphocytic leukemia test system (43). 

From another Dysidea sponge species, Dysidea avara, the sesquiterpenes avarol, Fig. (9) and avarone, Fig. (10), which show a wide variety of biological activities, were first isolated. Both compounds are potent antileukemic agents in vitro and in vivo. They were determined to be neither direct mutagens nor premutagens, and they displayed antimutagenic activity... 

It should be noted that while these compounds show potent in vivo antileukemic activity against P-388 leukemia in mice, very similar compounds, e g., roridin D, Fig. (61) show no in vivo activity. The key difference seems to be the presence of an oxygen substituent in the ring A of the trichothecene nucleus in the baccharinoids. More recently, screening of plants from South America for antineoplastic activity and subsequent assay-guided fractionation resulted in the isolation of several pentacyclic triterpenoids as active constituents from some Baccharis spp [85],... 

Yadanziosides F (93), I (94), J (95), and L (96) were demonstrated to have in vivo antileukemic activity against the murine P-388 lymphocytic leukemia. 

Many activities in quassinoid area were due partly to the fact these natural products possess a wide spectrum of biological properties including in vivo antileukemic, antiviral, antimalarial, antifeedant, and amoebicidal activity. 

Enocitabine is an antileukemic agent closely related to cytarabine. It appears more resistant to deamination than cytarabine, thus allowing greater in vivo phosphorylation into an active cytotoxic metabolite. 

A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivo antileukemic activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDFi mice as shown in Table 8. Bisbrusatolylmalonate (81), bisbrusatolylsuccinate (82), bisbrusatolylglutarate (83), bisbrusatolyladipate (84), and bisbrusatolyl sebacate (85) were as active as, or more active than, brusatol (8). The C-3 esters of brusatol (8) or bruceantin (1) were also as active as, or more active than, the original brusatol (8) and bruceantin (1) in general. 

To evaluate the effects on biological activity of variations in structure of the ester moiety, several semisynthetic esters of maytansinol were prepared. The propionate (230), bromoacetate (231), crotonate (232), and trifluoroacetate (233) esters of maytansinol (229) were made by procedures involving either anhydride-pyridine (230-232) or anhydride-acid (233) treatment. Fig. (58). TTie esters 228, and 230-232 were found to show antileukemic activity comparable to those of the naturally occurring substituted alanyl esters. The trifluoroacetate ester 233 showed no antileukemic activity, possibly because of ready solvolysis in vivo to inactive maytansides. 

The corresponding 5-methyluracil analog, l-(2 -deory-2 -fluoro-p-D-arabinofnranosyl)-5-methyluracil [FMAU] was found to be more potent in mice infected with Herpes simplex vims (HSV) types 1 and 2 without toxicity at effective dose levels. FMAU was also found to be active in vitro and in vivo against P-815 and L-1210 leukemia cell lines resistant to the antileukemic agent, 1-p-D-arabinofnranosyl-cytosine [Ara-C]. A Phase 1 trial of FMAU in patients with advanced cancer showed that drug-induced central nervous system (CNS) dysfunction was the dose-limiting toxicity (J). 

Some novel hexacyclic and 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized by Terasawa et al. They were evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclics 213 and 215 have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of the camptothecin moiety. They were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives of bicyclic amino ketone 212 or 214 and a tricyclic ketone 211, respectively (Scheme 46) (94JME3033). 

Waurzyniak, B., E.A. Schneider, N. Turner, et al. 1997. In vivo toxicity, pharmacokinetics, and antileukemic activity of TXU (anti-CD7)-pokeweed antiviral protein immunotoxin. Clin. Cancer Res. 3(6) 881-890. 

A series of bis-(brusatolyl) esters (55b) has been synthetized and tested for in vivo antileukemic activity. The bis-(brusatolyl) malonate, succinate, glutarate, adipate and sebacate were as active or more active than brusatol (55a) 51). 

DIC undergoes stepwise demethylatlon to 5-aminoimidazole-4-carboxamide (AIC)The monomethylated intermediate (10)75 or dlazomethane76 nay be the active metabolites of DIC. The imidazole-4-carboxamide li (BIC) is transformed into an ionic product 12 in vivo which may explain the differences in antileukemic action and resistance development of DIC and BIC. 5 Cytotoxicity sttidy and preliminary clinical trlals 6 of BIC are reported. The action of 5-diazoimidazole-4-carboxamide (8) was studied in rabbit platelets the sulfhydryl group and pyrophosphate structures may be involved in the mechanism of release of 5-hydroxytrypfamine by 8. ... 

We next examined in vivo antileukemic activity of SMDC compared with ara-C against implanted mouse leukemia P388 (10 ) in CDFl mice, with doses indicated in Table 3 given ip once each day on days 1-5. As described in Table 3, ara-C was much more potent than SMDC at every dose. We found that SMDC was not a substrate for cytidine deaminase from... 

In vivo antileukemic activity of CNDAC, cytarazid, and ara-C was also examined against ip-implanted P388 in CDFi mice (Table 8). CNDAC administered ip once a day on days 1 and 5 at 100 mg/kg had a T/C of 183%, while cytarazid and ara-C on the same... 

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