Antitumor activity alkaloids

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. 

Recent advances on antitumor-active benzo[c]phenanthridine alkaloids 99H(50)627. 

Representatives of all these distinct categories of charged or charge-separated species have been isolated from natural sources. Salts of cationic alkaloids are widespread in nature, among them pyridinium, quinolinium, and isoquinolinium alkaloids. Examples of monocationic alkaloids are Cryptaustoline (1) (Cryptocarya) and the antitumor active Avicine (2)... 

A cytotoxic alkaloid has been isolated from the filamentous species Hapalosi-phon forUinalis strain V-3-1. This isolate was made from soil samples collected in the Marshall Islands in 1981. This strain produces the lipophilic compound hapalindole A, which has a broad range of antialgal and antimycotic activity (9). OscUlatoria acutissima strain B-1, isolated from a freshwater pond in Oahu, was found to produce two novel macrolide compounds termed acutiphycin and 20, 21-didehydroacutiphycin. These macrolides show cytotoxicity (KB and NIH/3T3) and antitumor activity (Murine Lewis lung carcinoma) (10). 

However, the affinity of 43 was higher than that of the allylic derivative 72 and near to that of codeine, though 5-fold less (74). Recently, some naturally occurring hasubanan alkaloids have been submitted to screening for antitumor activity, but the results, as far as we know, remain obscure. 

Das has described the cycloaddition of camptothecin (92), an alkaloid with potent antitumor activity, with maleic anhydride under the action of microwave irradiation in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and 94, were produced. The first was formed by involvement of the B-ring in a hetero Diels-Alder reaction whereas the second was formed by involvement of the C-ring, probably through Diels-Alder reaction of intermediate 95 (Scheme 9.28). 

The polycyclic structure of manzamine A 74, an alkaloid with promising antitumor activity, constitutes an ideal testing ground for probing the effciency of RCM. Although no total synthesis of 74 has yet been reported, various approaches to this complex target rely on RCM-based strategies. 

The isolation of the antitumor agents vincaleukoblastine (1) and leuro-cristine (2) from Catharanthus roseus (L.) G. Don has proved to be one of the most important developments in both natural product chemistry and the clinical treatment of cancer during the 1960s to 1980s. More alkaloids (over 90) have been isolated from C. roseus than from any other plant, and because of the complexity of the alkaloid mixture this work has required the most advanced isolation and structure determination techniques. The exceptional interest in the broad spectrum of antitumor activity of these compounds has resulted in numerous achievements in the pharmaceutical, clinical pharmacologic, and therapeutical sciences. Simultaneously, strenuous efforts have been made in three areas of the natural product chemistry (i) elaboration of a practical semisynthesis of... 

Oxoleurosine (14) was evaluated for antitumor activity according to established protocols. No activity was observed in the dose range 0.25-6.25 mg/kg in the P388 lymphocytic leukemia system in mice, but the alkaloid was cytotoxic in the KB test system in vitro (EDjo 0.31 p.g/ml) (52). 

The 4-acyl derivatives of 4-deacetylvinblastine (98) are among the earliest semi-synthetic compounds prepared in exploring the medicinal chemistry of the bisindole alkaloids from Catharanthus. By 1965, the clinical utility of vinblastine (1) and vincristine (2) was firmly established, and the naturally occurring congeners leurosine (3) and leurosidine (4) had been well characterized with respect to their experimental antitumor activity. Since these compounds were substantially less active in animal tumor... 

Multiple single-point modification of both halves of the bisindole framework provided vinepidine (144), a bisindole alkaloid that exhibited experimental antitumor activity similar to vincristine without demonstrating the acute neuronal toxicity of this alkaloid. Ultimately, the vinepidine experience was both educational and an exercise in humility, since the compound showed promise in preclinical neurotoxicology models yet demonstrated considerable neurotoxicity in clinical trials. Nevertheless, vinepidine brings a rich example of the combined effects of ring D conformation (with its associated effect on N-6 basicity) and the presence of an N-1 formyl group. 

Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983)... 

The strong interest in the synthesis of pyrido[4,3-h]carbazole alkaloids started in the late 1960s with the disclosure of the antitumor activity of ellipticine (228) and 9-methoxyellipticine (229) (see Scheme 2.56) in several animal and human tumor systems. This discovery made these alkaloids to important synthetic targets and induced extensive studies of structure modification. These synthetic efforts have... 

The plethora of piperidine (242) and pyrrolidine alkaloids in Nature have made attractive targets for total synthesis, particularly since many contain a hydroxyl moiety adjacent to the amino group. This functionality is the case with the pseudodisto-mins-piperidines with antitumor activity isolated from the Okinawan tunicate Pseudodistoma kanaka. The limited availability of the natural material has prompted... 

Sesbanine (608), a unique alkaloid isolated from Sesbania Drumondii seeds, which seems to exhibit potent antitumor activity, has been synthesized by prior carefull exploration for pyridine tertiary amide metalation (Scheme 179) (83TL2649). In the optimum case, LiTMP metalation of the diisolpropyl amide 447b for 15 min. followed by condensation with 3-... 

Among the carbazole alkaloids the most noteworthy is ellipticine (28). It and a number of synthetic analogs exhibit significant antitumor activity. The mechanism of action is believed to involve interaction with DNA (79MI30602). 

The tribrominated bisindole alkaloid dragmacidin (30) from the marine sponge Dragmacidon sp. has antitumor activity against P-388 cells (IC5o 15 pg/ml), A-549 (human lung), HCT-8 (human colon), and MDAMB (human mammary) cancer cell lines (IC501-10 pg/ml) [43]. 

The ecteinascidins constitute a group of very complex alkaloid tris(tetrahydroisoquinolines) with potent in vivo antitumor activity and were isolated from the colonian Caribbean tunicate Ecteinascidia turbinata. The compounds are abbreviated as Et followed by a number that represents the value of the highest mass ion observed in the (+)-FABMS. Reports of the potent in vivo activity of extracts of that tunicate date back to 1969, when it was reported that such extracts gave T/C values of up to 272 vs P388, with four of six cures in one experiment, and they were also found to be powerful immunomodulators [72]. After a decade of effort, two research groups reported at the same time the structures of four [Et 743 (1), Et 729 (63), Et 745 (64), and Et 770 (66)] [72] and two [Et 743 (1), Et 729(63)] [73] ecteinascidins, respectively. The development of an isolation process that was efficient on a large scale allowed Rinehart s group to obtain additional ecteinascidins, Et 743 V2-oxide (67), Et 722... 

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