Alkaloids anticancer activity

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). 

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). 

Vincristine is a naturally occurring alkaloid that has significant anticancer activity. It is isolated from a plant closely related to the periwinkle, a common ornamental plant of tropical and temperate regions. 

Sanguinarine 1 is the prototype of benzophenanthridine alkaloids which occur frequently in plants of the family Papaveraceae. It has anticancer activity and has become of commercial interest because of its antibacterial properties. It is known from biosynthetic studies that protopine 2 is a metabolite on the pathway to sanguinarine, and recent work has shown that a microsomal cytochrome P-450 NADPH dependent enzyme will hydroxylate protopine... 

Because of the postulated biosynthetic derivation of the Cephalotaxus alkaloids from the Homoerythrina bases, the former, relatively new group is included in this chapter. Anticancer activity has been found in certain members of the Cephalotaxus group, so the subject has already been reviewed several times (7-9). Annual coverage is given to the Erythrina, Homoerythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports of the Chemical Society (10-1 la). 

The total synthesis of alkaloids of the cephalotaxine type has attracted considerable attention (75) because of the anticancer activity reported for certain derivatives (100) (see Section IV,A). The first synthesis of cephalotaxine (105a) was reported by Auerbach and Weinreb (155, 156), closely... 

Alkaloids o Anopterus Species (Escalloniaceae) Anopterimine, Anopterimine iV-Oxide, Hydroxyanopterine, and Dihydroxyanopterine.—Some Australian workers41,42 have studied the alkaloids of Anopterus macleayanus F. Muell. (Queensland) and A. glandulosus Labill. (Tasmania). Extracts of these plants have shown some preliminary anticancer activity. 

The toxic effects observed with intact animals has its counterpart in the cytotoxic effect, which has been recorded for nearly 180 alkaloids (Table III). These data have been obtained by screening many natural products for anticancer activity. However, an alkaloid that can kill a cancer cell is usually also toxic for normal cells. Therefore, the data shown in Table III are another indication of the general toxicity of alkaloids toward animals. Because this toxicity applies also for herbivores, the production of alkaloids by plants can certainly be interpreted as a potent antiherbivore mechanism. 

There have been numerous papers related to the total synthesis of bicyclic alkaloids, such as pyrrolizidines, indolizidines, and quinolizidines, because of their interesting biological activities (e.g., anticancer activity). 

Taxus (yew) trees contain alkaloids called taxanes that have anticancer activity and are the basis of the semisynthetic anticancer drugs paclitaxel and docetaxel (see separate monographs), which are based on taxol, from Taxus brevifolia. 

Extracts of some amaryllids, as well as alkaloids isolated therefrom, have exhibited various biological activities. These activities cover central nervous system, antitumor, antiviral, antibacterial, anti-inflammatory and antiparasitic conditions 8, 18, 52, 53, 54). However, the more recently demonstrated potent anticancer activity of pancratistatin 14 and the selective, reversible acetylcholinestrase (ACHE) inhibitory activity of galanthamine 5 has fuelled the search for bioactive Amaryllidaceae alkaloids toward the development of antitumor and anti-Alzheimer s drags 55). 

A large number of steroidal alkaloids have been described in the literature. Recent reviews covering Solatium alkaloids [619] and the anticancer activity of solasodine glycosides [620] are available. 

Homoharringtonine (HHT) (19) is an ester derivative of the parent alkaloid cephalotaxine (20), which has an unusual tetracyclic ring system. Cephalotaxine was isolated from two Cephalotaxus species" and its final structure was assigned by X-ray crystallography." HHT was isolated in 1970 by workers at the USDA laboratories in Peoria" but its anticancer activity was first recognized by Chinese investigators. 

---