Alkaloids pyridoacridine

Dihydrothiazoloquinoline is a key intermediate in the synthesis of natural sulfur-containing pyridoacridine alkaloids—kuanoniamines and derdercitins, where the starting dienone is converted after a multistep reaction sequence to an a-bromo-ketone, which in turn was cyclized with thiourea to the desired dihydrothiazoloquinoline, photochemically convertible to the final alkaloid derivatives 39 (Scheme 21) (92JA10081, 95TL4709, 95JA12460). 

Two new polycyclic pyridoacridine alkaloids, arnoamine B, 289, and its demethylated analogue, arnoamine A, have been isolated from the ascidian Cystodytes sp. These new compounds are the first known examples of pyrroles fused to pyridoacridines, have antifungal properties, and are cytotoxic in several human tumor cell lines <1998JOC1657>. Both these compounds have been synthesized, starting from the hydrazone 290 with a Fischer indole synthesis (Scheme 73) <2000JOC5476>. 

Molinski, T. F. 1993. Marine pyridoacridines alkaloids Structure, synthesis, an biological chemistry. Chemical Reviews, 93 1825-1838. 

Ciufolini, MA. Shm, Y.-C. Bishop, M.J. (1995) A unified strategy for the synthesis of sulfur-containing pyridoacridine alkaloids antitumor agents of marine origin. J. Am. Chem. Soc., 117,12460-9. 

The pyridoacridine alkaloids, kuanoniamines A-D (133-136) were isolated from an unidentified Micronesian tunicate and its nudibranch predator, Chelynotus semperi. The structures were established by extensive NMR spectral analysis. Cytotoxicity against KB cells ranged from IC50 values >10 ig/mL for kuanoniamine B (134), 5 ig/mL for kuanoniamine D (136), to 1 ig/mL for kuanoniamine A (133) [145]. Kuanoniamine A (133) has also been synthesised [146,147]. 

Spanish workers have recently described a rapid method for the construction of pyridoacridines which could be of value for the synthesis of a range of cytotoxic pyridoacridine alkaloids. Thus, treatment of MEM-protected 4-quinolone 1 with 3 equivalents of LDA in THF, first at -78°C then with stirring at room temperature, followed by addition of 1 equivalent of methyl 3-formyl-2-pyridinecarboxylate gave, after quench with aqueous ammonium chloride and chromatography, a mixture of the tetracycles 2 (15%) and 3 (20%). Oxidation of either 2 or 3, or a mixture of 2... 

Molinski, T. F., Marine pyridoacridine alkaloids structure, synthesis, and biological chemistry, Chem. Rev., 93, 1825, 1993. 

Ding, Q. Z., Chichak, K., and Lown, J. W., Pyrroloquinoline and pyridoacridine alkaloids from marine sources, Curr. Med. Chem., 6, 1, 1999. 

Gunawardana, G. P., Koehn, F. E., Lee, A. Y., Clardy, J., He, H., and Faulkner, D. J., Pyridoacridine alkaloids from deep-water sponges of the family Pachastrellidae structure revision of dercitin and related compounds and correlation with kuanoniamines, J. Org. Chem., 57, 1523, 1992. 

Porphobilinogen and Studies of Its Biosynthesis, ft. Neier. Synthesis and Cycloaddition Reactions of Iso-Condensed Heteroaromatic Pyrroles, C. K. Sha. Azacyclopentadienyl Metal Compounds Historical Background and Recent Advances, C. Janiak and N. Kuhn. Recent Developments in the Synthesis of Marine Pyridoacridine Alkaloids, A. M. Echavar-ren. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates, D. L. Comins and S. P. Joseph. Index. S S... 

Structure, synthesis, and biochemistry of marine pyridoacridine alkaloids 93CRV1825. 

Delfourne E, Bastide J. Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents. Med. Res. Rev. 2003 23 234-252. 

Pyridoacridine alkaloids have been isolated from sponges ascidians, anemones, and a prosobranch. Two thiazole-containing compounds were obtained, namely kuanoniamine E, 429, and kuanoniamine E, 430 <2002JNP1198>. 

Gellerman, G., Rudi, A., Kashman, Y. Synthesis of pyrido[2,3,4-kl]acridines. A building block for the synthesis of pyridoacridine alkaloids. Tetrahedron Lett. 1992, 33, 5577-5580. 

Pyridoacridine alkaloids isodiplamine and lissoclinidine. Copp and co-workers reported the isolation of two new pyridoacridine analogues, isodiplamine (97) and lissoclinidine (98) from the New Zealand ascidian Lissoclinum notti. The authors utilized 6 Hz optimized HMBC data in the process of characterizing these novel... 

Among the pyridoacridine alkaloids, meridine 50 and cystodamine 51 exhibit this ring skeleton (see Section II,D,1 on pyrido[2,3,4-k/]acridines). This ring pattern can also be observed in quino[a]acridines 6 and 9 and triquinobenzene 5 (see Section II,A,1 on pyrido[2,3-a]acridines). 

Eilatin 33 and eudistone A 48 and B 49 are pyridoacridine alkaloids that possess this ring skeleton. This ring system is also found in a synthetic isomer, isoascidemin 77, of ascididemin 28 (see pyrido[h]acridines and pyrido[2,3,4-fcf]acridines). Three other alkaloids, the plakinidines (A-C) 78-80 from Plakortis sponge, also share this ring system (90JA1,90TL3271). 

The pentacyclic pyridoacridine alkaloids (amphimedine 105, neoamphi-medine 106, petrosamine 107, and debromopetrosamine 108) also contain this ring skeleton (see pyrido[2,3-4-/c/]acridines). 

Nitrene insertion. A nitrene insertion reaction is central to many syntheses of pyridoacridine alkaloids and their analogues. For example, Labarca et al. [87JCS(P1)927] have reported a three-step synthesis of a pyridoacridine 169 starting from 2-methoxyacridine-9-carboxaldehyde 165 (Scheme 26). Cyclization of the vinyl azide 166 by thermolysis is believed to involve a nitrene insertion reaction, to give either 167 or 168. 

The same strategy has been applied to the preparation of a number of pyridoacridine alkaloids, which include 2-bromoleptoclinidone 29 (90LA205), 11-hydroxyascididemin 30 (93H943) and kuanoniamine A 146 (93H943), and also for the synthesis of neocalliactine acetate 139 (92LA1205 93H943) (a derivative of calliactine 32). 

Pyridoacridines are characterized by an 1 lH-pyrido-4,3,2-acridine moiety and have only been reported to occur in marine organisms [86]. Marine invertebrates, such as sponges and tunicates, are often brightly coloured due to the presence of pyridoacridine alkaloids. The colours exhibited by the pyridoacridines may vary according to differences in pH. This physico-chemical property is related to the two basic nitrogens in the aromatic ring systems. These alkaloids exhibit a variety of biological activities, e.g. cytotoxicity [86], inhibition of topoisomerase II [87], anti-HIV activity [88], release of Ca2+ [89], and intercalation of DNA [90]. 

The pyridoacridine alkaloids isolated from the Micronesian sponge Oceanapia sp. were tested for insecticidal activity, cytotoxicity properties, as well as for their ability to bind to adenosine receptors and to benzodiazepine binding sites of GABAa receptors [91]. Kuanoniamines C... 

---