The Aristolochic Acids and Aristolactams

Aristolochic acids and aristolactams occur mostly within the family of Aristolochiaceae, although cepharanone-A and aristolactam-Bll were found in Stephania cepharantha Y. Hayata (Menispermaceae), and doryflavine was obtained from Doryphora sassafras Endlicher (Monimiaceae). There is a possibility that aristolochic acid-B may correspond to aristolochic acid-D. 

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The PMR spectra of the aristolochic acids and aristolactams are usually run in DMSO-de. Pyridine-dg has also been used in connection with the aristolactams. 

Plants belonging to the genns of Aristolochia are rich in aristolochic acids and aristolactams. 

Aristolochic acids and aristolactams possess skeleta (66) and (67), respectively, and are often found in the same plant. The aristolochic acids are among the small group of natural products incorporating a nitro-function. Compounds belonging to these two classes are non-basic, but can nevertheless be classified as alkaloids since they are derived from in vivo oxidation of aporphines. The last review on this dual topic appeared in 1961. ... 

Kampo medicines in which A.fangchi root or A. manshuriensis stem may be misused [492], Moreover, LC-PDA and LC-EIMS detection methods both were effective in distinguishing AAI (5) and AAII (5) peaks by their spectra. Very recently, we have reported the extensive analysis of aristolochic acids and aristolactams in the various Chinese medicinal plants and crude drugs using different techniques. A method has been developed using reversed phase liquid chromatography coupled with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry under the positive ion detection mode [LC/(+)APCI/MS/MS] to determine the amount of AA-1(5) in Xinxin, a traditional Chinese medicine that originate from nine Asarum species... 

The dried roots of this plant contain, other than magnoflorine described in Section 1.6, aristolochic acid-I, which possesses a very rare nitro moiety [1]. From other plants in the genus Aristolochia, other than aristolochic acid-I, at least 14 related alkaloids, each of them possessing a nitro moiety, such as aristolochic acids II-IV, were isolated [2].These alkaloids are often isolated with their corresponding laaams (aristolactams). As described sub-sequendy, the aristolactams can be easily formed from the aristolochic acids, and these lactams might be formed during the extraction process. Aristolochic acid-I was synthesized by the application of a photochemical reaction [3]. 

Fig. 32.15. Biogenesis of aristolochic acids and aristolactams (modified from Cordell, 1981 used by permission of the author).

The IR spectra are useful for detecting functional groups of Aristolochia alkaloids. Aristolochic acids show two characteristic bands at 1550 and 1350 cm due to the absorption of nitro group, and the carboxy OH group appears at 3000-2500 cm as a broad continuous absorption. Hydroxy derivatives of aristolochic acids or aristolactams show OH and NH absorptions at 3300-3500 and 3200-3400 cm The carboxy or lactam carbonyl is present at 1690 cm i. In general, the aromatic ring system shows stretches at 1625-1575 and 1525-1475 cm 1 as usual, and observation of the 900-700 cm region is often used for analysis of substitution type in aromatic derivatives 28). 

Over the last seventy years over sixty species of Aristolochia have been exploited for chemical examination by research groups throughout the world and a variety of compounds have been isolated. The spectrum of physiologically-active metabolites from Aristolochia species covers 14 major groups based on structure aristolochic acid derivatives, aporphines, amides, benzylisoquinolines, isoquinolones, chlorophylls, terpenoids, lignans, biphenyl ethers, flavonoids, tetralones, benzenoids, steroids, and miscellaneous. The aristolochic acid derivatives, host of phenanthrene derived metabolites were further classified into aristolochic acids, sodium salts of aristolochic acids, aristolochic acid alkyl esters, sesqui- and diterpenoid esters of aristolochic acids, aristolactams, denitroaristolochic acids, and aristolactones. The terpenoids can further be subdivided into 4 groups mono-, sesqui-, di- and tetraterpenoids. 

Aristolactam (13) (in some papers, aristololactam) was first prepared by catalytic hydrogenation or zinc reduction in acetic acid from aristolochic acid I (25). It has been isolated from seveizl Aristolochic plants, including A. debilis and A. fangchi (24). Kupchan and Merianos isolated the first aristolactam iV-glucoside (19) from A. indica (37). 

Aristolochic acid (60), aristolochic acid-D (61), and aristolactam-/3-D-glucoside (62), reported by earlier workers, have been re-isolated from Aristolochia indica (Aristolochiaceae). Of greater interest, five phenanthrene derivatives, (63)—(67), were also found in the plant. Compound (65) was labelled aristolamide, (66) is aristolinic acid methyl ester, and (67) is methyl aristolochate.71... 

Aristolochic acid I and aristolochic acid II are mutagenic in several test systems. A mixture of these two compounds was so highly carcinogenic in rats that even homeopathic Aristolochia dilutions have been banned from the German market. The closely related aristolac-tam I and aristolactam II have not been submitted to carcinogenicity testing, but these compounds similarly show mutagenic activity in bacteria. 

On the other hand, AA are activated by nitroreduc-tion in aristolactams which form DNA adducts with adenosine and guanosine. The formation of AA-DNA adducts was studied in intro cytochrome P450 lAl and 1A2 [57] as well as prostaglandin H synthetase [58] were shown to be involved in the metabolic activation of AA. These observations could explain variations between individuals in the susceptibility to aristolochic acid toxicity as well as the preferential localization in the kidney and the urinary tract. Carcinogenicity of AA DNA adducts has been related to the mutation in the codon 61 of the protooncogen Ha-ras [59] as well... 

Although the precise mechanism of aristolochic acid-induced nephropathy and urothelial carcinoma is yet to be characterized, recent data indicate direct DNA damage may be the cause. The major components of aristolochic acid are metabolized to mutagenic compounds called aristolactam I and aristolactam II, respectively, which have been demonstrated to form DNA adducts in humans. Direct cellular toxicity is an unlikely mechanism of injury since the onset is delayed and progression of renal failure continues after aristolochic acid exposure. ... 

The term aporphinoids covers aporphines and their close biogenetic precursors, the proaporphines. Alkaloids derived from relatively straightforward biological transformations of proaporphines or of aporphines are also encompassed, so that proaporphine-benzylisoquinolines, aporphine-benzylisoquinolines, aporphine-pavines, oxoaporphines, dioxoaporphines, aristolactams, and aristolochic acids, as well as phenanthrenes, will be discussed. Azafluoranthenes are also included within the scope of aporphinoids for reasons which will become clear toward the end of the present chapter. 

Indole and isoquinoline alkaloids continue to play a dominant role. The apor-phinoids, comprising proaporphines, aporphines and related dimers, are treated separately, partly in order to reduce the burden on contributors aristolactams and aristolochic acids, which have not been reviewed since 1961, also are discussed in this chapter. This year the quinolizidine alkaloids, including the sesquiterpenoid Nuphar bases and the appropriate Lythraceae alkaloids, as well as azaphenalenes of plant and insect origin are reviewed together. Amaryllidaceae, Erythrina, imidazole, purine and peptide alkaloids are omitted from this volume, but it is expected that the chemistry of these groups covering the period 1974—1976 will be surveyed in Volume 7. 

Aristolactams were regarded as intermediates in the biosynthetic pathway of aristolochic acid, which was produced by aporphines via oxidation process. Eleven aristolactams were isolated from Fissistigma. Piperolactam A (A-95), piperolactam C (A-96), aristolactam AIHa (A-97), aristolactam BII (A-98), and agoniothalactam (A-99) were isolated from F. balansae [49]. Aristolactam FII (A-100), stigmalactam (A-101), aristolactam All (A-102), enterocarpam I (A-103), and velutinam (A-104) were isolated from F. oldhamii [49]. Aristolactam Bill (A-105) was isolated from both the species [49]. 

Kamatsh and co-workers reported that growth of mouse sarcoma-37 cells incubated with aristolochic acid (5) at concentration of 100-200 pg/ml for 3 hours was completely inhibited. Treatment of mice with aristolochic acid (5) (1.25-5 mg/kg ip per day) for 3 days, after subcutaneous implantation of sarcoma-37 cells inhibited tumor growth by 40-50 %. The cytotoxicity on HeLa cells in culture was observed at concentration of 25 pg/ml [415]. The acute toxic effects of aristolochic acid I (5) were observed in rats and mice, oral or intravenous administration of high doses was followed by death from acute renal failure within 15 days [416], The biological activities of aristolochic acid I (5), aristolactam I... 

Aristolochic acid I (5) was also reported to exhibit antibacterial action against Staphylococcus aureus, Diphococcus pneumoniae and Streptococcus pyogenes in infected mice at 50 pg/kg ip [415]. When, rats with wounds infected with S. aureus were treated intraperitoneally or orally with aristolochic acid I (5), they recovered much faster than control. In mice with Pneumococci infections were influenced very well by aristolochic acid I (5). Rabits after intravenous application of aristolochic acid I (5) showed an increased antibacterial action of serum. Aristolactam la (64) and aristolochic acid I (5) showed antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, S. faecalis, S. aureus and S. epidermides [191]. Neurological disorders, especially Parkinson s diseases have been treated by the administration of the aristolactam taliscanine (91) to the affected patient [439]. Cepharadione A (107) exhibited antimicrobial activities [440],... 

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