Aristolochic acids

Tritiated samples of stephanine (49) and (at a lower level) prestephanine (48) were incorporated into (50) in Aristolochla bracteata. Orientaline (47) was shown to be a specific precursor, with the (R)-isomer preferred over the (S)-isomer. Nororlentaline (46) was shown to be a specific precursor but, since its level of incorporation was approximately ten times lower than that of (47), 

In accord with normal experience in experiments with isoquinoline alkaloids (c . Vol. 11, p.l2), administered dopa was 

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Aristolochic Acid. Rosenmund and Reichstein prepared their material from roots and rhizomes of A. Sipho. It has the formula Cj HjiO N, m.p. 275° (dec.), and forms a methyl ester, m.p. 280° (dec.), [a]n 0°, which is difficult to saponify and on. hydrogenation gives a bright yellow substance, m.p. 312°, which forms a diacetyl... 

A. indica L. Indian Aristolochia, also known as Indian birthwort, ishvara (Sanskrit), or adagam (Tamil), is a bitter climber native to India. The medicinal material consists of the rhizome, which is to resolve inflammation (India), counteract insect poison, and as an antipyretic (Philippines and Vietnam). The rhizome contains aristolochic acid, which inhibits in vitro and dose-dependent phospholipid hydrolysis by the human synovial fluid phospholipase A2, snake venom phospholipase A2, porcine pancreatic phospholipase A2, and human platelet phospholipase A2 (2). 

The plant is known elaborate a series of quite unusual phenanthrene alkaloid derivatives, of which aristoliukine-C, aristofolin A and E, aristolochic acid-la methyl ester, and aristolochic acid. Other chemical constituents found in this plant are flavonoid glycosides such as kaempferol-3-O-rutinoside and quercetin kaempferol-3-O-rutinoside (3,4). Exposure to Aristolochiaceae family is associated with the development of cancer in humans. A significant advance is the toxicological effects of aristolochic acid has been provided by the work of Pezzuto et al. They showed that aristolochic acid is a mutagen... 

Vishwanath BS, Fawzy AA, Franson R, et al. Edema-inducing activity of phospholipase A2 purified from human synovial fluid and inhibition by aristolochic acid. Inflammation 1988 12 549-561. 

Wu TS, Leu YL, Chan YY. Aristofolin-A, a denitro-aristolochic acid glycoside and other constituents from aristolochia kaempferi. Phytochemistry 1998 49 2509-2510. 

Pezzuto JM, Swanson SM, Mar W, Che CT, Cordell GA, Fong HH Evaluation of the mutagenic and cytostatic potential of aristolochic acid (3,4-methylenedioxy-8-methoxy-10-nitrophenanthrene-l-carboxylic acid) and several of its derivatives. Mutat Res 1988 206 447-454. 

Penicillins Proton pump inhibitors Chronic interstitial nephritis Cyclosporine Lithium Aristolochic acid Renal vasculitis, thrombosis, and cholesterol emboli ... 

In 2001, the FDA found that a number of botanical products brought to its attention contained aristolochic acid, a chemical that has been implicated in kidney disease. The agency advised consumers to discontinue the use of any supplement that contained this chemical. 

Tree sparrow Passer Swallowtail butterfly Aristolochic acids (from Aristolochia Nishida and... 

Nishida, R. and Fukami, H. (1989). Ecological adaptation of an Aristolochiaceae-feeding swallowtail butterfly, Atrophaneura alcinous, to aristolochic acids. Journal of Chemical Ecology 15,2549-2564. 

Aristolochic acids, representatives of the substituted 10-nitrophenanthrene-l-acids, have been known since 1943, when Rosenmund and Reichstein first isolated aristolochic acid I (1) from A. clematitis (23) [this compound was named aristolochic acid A by Tomita and Sasagawa (24)]. Its structure was elucidated by Pailer et al. in 1956 by means of chemical reactions (25), and when several aristolochic acids—aristolochic acids II (2) (aristolochic acid B by Tomita), III (3) Ilia (4) (aristolochic acid C by Tomita), IV (5), and IVa (6)—were isolated from the root of A. clematitis by Pailer and his co-workers (26) and in the meantime from A. debilis and A. fangchi by Sasagawa (27). 

Aristolochic acid derivatives have been found only among plants of the family Aristolochiaceae (Aristolochia spp. and Asarum canadense var. reflexum (34)) and in Bragantia wallichii (35,36). In all derivatives, substitution of nitro group is present at C-10, the carboxy group is present at C-1, and a methylenedioxy is substituted at C-3 and C-4 only. This general structure will be very interesting in biosynthesis and plant biochemistry. 

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). 

The biosynthesis of aristolochic acids is considered to begin with 1-ben-zyltetrahydroisoquinoline precursors and to proceed via aporphine intermediates (5). In radioactive labeling studies, Spenser and Tiwari infused d/-tyrosine-2- C into the stem of A. sipho. The C-labeled aristolochic acid I formed lost more than 60% of its radioactivity when it was decarboxylated to the corresponding nitro phenanthrene derivative. Administration of d/-dihydroxyphenylalanine-2- C re-... 

C-labeled aristolochic acid I with the carboxy group containing 60% of the radioactivity (52). 

The phenolic derivatives of this series, such as aristolochic acid la and 4,5-dioxoaporphine, suffered considerable bathochromic shifts, and further shifts toward the longer wavelength region are observed on addition of alkali. For instance, the UV spectrum of 4,5-dioxoaporphine (49), 246 (4.70), 292 (4.14), 305 (4.26), 318 (4.28), 459 (4.23), shifts to 241 (4.71), 256 (4.67), 305 (4.21), 331 (4.25), 510 (4.30) in alkaline solution (64). This bathochromic shift was also found in aristolochic acid la (50) (63, 65). The UV spectroscopic method has been used for the quantitative analysis of aristolochic acids from plants or pharmaceutical products (66-68,71). 

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). 

The mass spectra of Aristolochia N-containing compounds were first reported by Pailer et al., who studied the electron impact-induced fragmentation of the esters of aristolochic acids. They found that the nitro radical is very easily split off from the molecular ion, giving the base peak (M — 46) +, and then the CH3, CO, etc. were removed. Pailer etal. concluded the fragmentation was as shown in Scheme 3 (26). 

Aristoloside, an aristolochic acid derivative, was isolated from a stem of A. 

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