Alkaloids, anticancer

Campthoteca acuminate Campthotecin Quinoline alkaloid Anticancer... 

A large body of experimental data has been accumulated on the solubility and extractability of natural products, such as steroids, alkaloids, anticancer agents, oils from seeds, and caffeine from coffee beans, in various SCF solvents such as CO2, ethane, ethylene, and N2O. Carbon dioxide is probably the most widely investigated SCF solvent since its critical temperature T = 31.1°C) makes it an ideal solvent for extracting materials that are thermally labile. Also, CO2 is nontoxic, nonflammable, environmentally acceptable, and inexpensive. 

Rabbani-Chadegani A, Chamani E, Hajihassan Z. The effect of vinca alkaloid anticancer drug, vinraelbine, on chromatin and histone proteins in solution. Eur J Pharmacol 2009 613(l-3) 34-8. 

Two vinca alkaloid anticancer drugs (vincristine and vinblastine) and two precursors (catharanthine and vindoline) were extracted fixm periwinkle leaves and separated on a Cjg column k = 2S4 nm). Good resolution and complete elution were achieved in 15 min using a 62/38/0.3 water (0.1M phosphate buffer at pH 4.14)/acetonitrile/acetic acid mobile phase [1395a]. Linear response was reported over the range from 0.25-25 pg injected. 

Many other bisben2ylisoquinoliae alkaloids, such as tetrandriae (80), from Cjcleapeltata Hook., are also known. Compound (80), for example, although it causes hypotension and hepatotoxicity ia mammals, ia other tests, possessed enough anticancer activity to be considered for preclioical evaluation (55). The arrow poison tubocurare prepared from Chondrendendron spp. also contains the bisben2yhsoquiQoline alkaloid tubocurariae (9). 

Vindoline [2182-14-1] (45), a monomeric Vinca alkaloid intermediate important in the synthesis of antineoplastic alkaloids, is selectively converted in good yield to 0-desmethylvindoline [68687-22-9] (46) by cultures of Sepedonium chrysospermum (17,25), whereas Streptomyces albogriseolus removes only the A[-methyl group to give (47) (91) (see Chemotherapeutics, anticancer). 

Isolation, synthesis, and possible mechanism of action of anticancer alkaloid camphotecin and related alkaloids 99YGK181. 

The protected E-ring moiety of (S)-camptothecin has been prepared in enantio-merically enriched form by the enzymatic resolution of a triester with PLE in a pH 7 phosphate buffer-acetonitrile (5 1) solution (Figure 6.7). The alkaloid camptothecin is an inhibitor of the enzyme topoisomerase and some of its derivatives are anticancer drugs [52]. 

Quetin-Ledercq J (1994) Potential anticancer and antiparasitic indole alkaloids. J Pharm Belg 49(3) 181-192... 

Two deoxygenations of naturally occurring compounds have been reported. Anhydrovinblastine, an important intermediate for the anticancer drug navelbine, was prepared by Doris and coworkers from leurosine, an abundant alkaloid from the Madagascan periwinkle Catharantus roseus, in 70% yield by using Cp2TiCl (Scheme 5) [46]. 

A combination of a reductive amination and a Michael addition has been used to synthesize the anticancer alkaloid camptothecin (2-955) via 2-954, starting from the quinoline carbaldehyde 2-953 and benzylamine (Scheme 2.214) [487]. 

Xanthates serve as a reliable source of electrophilic radicals, and this was exploited by Zard and coworkers for a short synthesis of ( )-matrine (3-304), a naturally occurring alkaloid which has been claimed to have anti-ulcerogenic and anticancer properties [116]. Heating a mixture of xanthate 3-299 and the radical acceptor 3-300 (3 equiv.) in benzene in the presence of lauroyl peroxide as initiator, gave 3-301 in 30% yield and a 3 1 mixture of the tetracylic products 3-302 and 3-303 in 18% yield (Scheme 3.76) [117]. The three compounds could be converted into the... 

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

Lavie, Y., Harel-Orbital, T., Gaffield, W. and Liscovitch, M. (2001). Inhibitory effect of steroidal alkaloids on drug transport and multidrug resistance in human breast cancer cells. Anticancer Res., 21, 1189-1194. 

Other anticancer agents have distinct mechanisms paclitaxel and its relatives target microtubules as do the vinca alkaloids. Antiestrogens and antiandrogens target estrogen and androgen receptors. 

Camptothecin (Fig. 4), a quinoline alkaloid, is a potent anti-neoplastic agent that inhibits DNA topoisomerase I. Accumulation of up to 8 mg of camptothecin/L was reported for hairy root cultures of Ophiorriza pumila transformed with A. rhizogenes. Cotyledon-derived calluses of Nothapodytes foetida were able to produce not only camptothecin, but also its derivatives also known to exhibit anticancer activity. 

One of the major difficulties in the synthesis of these binary indole-indoline alkaloids is the necessity of generating the natural PARF (priority antireflective) (12) relative stereochemistry between C-14 and C-16, as well as the requirement for controlling the absolute stereochemistry at C-16, which must be (5). Other epimers at these positions lack the high cytotoxicity, with mitotic arrest at metaphase, that is the basis of the anticancer activity of these compounds (13,14). 

That only the wrong C-16 diastereomer seemed to be produced in this reaction was then demonstrated by the Kutney group, who prepared a series of binary indole-indoline alkaloids using the chloroindolenine approach. The apparent simplicity of this coupling reaction and the rapidity in assembling such binary alkaloids prompted an extensive study of reaction conditions (28), with the desire to find a procedure suitable for generation of the C-16 (S) isomer, required for anticancer activity. Despite the intensive effort involved in this in-depth study, no success could be realized, and it was therefore widely accepted that .. . it is very unlikely that any natural dimer could be obtained in this way (7). At this point it may be noted, however, that we were able to show subsequently that the desired C-16 -C-14 PARF relative stereochemistry can be obtained as a preferential result, albeit only in very low yield [3.6% PARF versus 2.1% PREF (priority reflective)], when the chloroindolenine reaction with vindoline is initiated with silver tetrafluoroborate (13). 

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