Pyrroloquinazolines

The origin of the non-anthranilic acid moiety is still controversial. It was found that, in Adhatoda vasica, C-1, C-2 and N-10 of vasicine are derived from aspartic acid (118) and C-3 and C-3 a from a Cj-unit (97,216). 

In Peganum harmala, [2- C]-ornithine (119) and labeled proline, putrescine, and related compounds are more or less specifically incorporated into the pyrrolidine ring system of vasicine 127, 128). This result suggests that ornithine is decarboxylated affording putrescine, a symmetrical molecule, which is then incorporated, a process which results in equal labeling at C-1 and C-3 a. The results can be rationalized by postulating that a symmetrical intermediate such as putrescine is involved 

The paths of the interconversions which occur among the alkaloids of Peganum harmala have also not been elucidated so far. Such studies have been hindered by the rapid metabolism of these compounds. After feeding pH]-vasicine, the label was detected in vasicinone and deoxyvasicinone. As only 65% of the administered radioactivity was recovered, it is possible that vasicine may have been degraded in the plant. Pegamine (6) is a potential intermediate for deoxyvasicinone (42). 

Adhatodine, vasicoline, vasicolinone, anisotine and sessiflorine may arise from pyrroloquinazolines and derivatives of anthranilic acid. 

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Reaction of anthranilonitrile or methyl anthranilate with 3-hydroxy-2-butanone followed by malononitrile gave the pyrrolo [1,2-a] quinazoline 16 (79AP552). Both of the diazine and azole rings of pyrroloquinazolines were also simultaneously formed by cyclization of the anilide 17 derived from 3-chloropropionic acid and 2-aminobenzophenone with potassium cyanide to afford the pyrrolo [1,2-a] quinazoline 18 (68JHC185 71USP3595861). 

The synthesized pyrroloquinazoline alkaloid as shown in Fig. 23 selectively inhibited COX-2 (IC5o = 1.2 pM) over COX-1 (IC50 > 10 pM) activity in human monocyte assays. In a purified ovine enzyme assay, the COX-1 activity was not affected even at a concentration over 50 pM compared to an IC50 value of 20.5 pM for COX-2 inhibition. The LOX efficacy was demonstrated by measuring LTB4 production in a mouse air pouch model [148]. 

Triazole acyl-tripeptides, (HI), prepared by McComsey (4) and aminomethyl-pyrroloquinazoline derivatives, (IV), prepared by Maryanoff (5) were effective as PAR-1 antagonists and used for treating PAR-1-mediated disorders. 

Reaction of an/iyi/ro-3-hydroxy-2-phenylthiazolo[3,2-c]quinazolin-4-ium hydroxide (459) with ethyl acrylate in boiling xylene overnight gives pyrroloquinazoline (461a) and carbonyl sulfide. The reaction, when carried out for 5 hr in the absence of solvent (xylene), furnished a 1 1 cycloadd uct, AH-5,6,7,7a-tetrahydro-7-ethox ycarbonyl-5-phenyl-5,7a-... 

When lithium aluminum hydride was applied, besides reduction of the C-4—N-5 double bond, the ester group was converted to a hydroxymethyl group. S By reaction with dry formic acid under reflux conditions, the pyrroloquinazoline-2-carboxylates 63 yielded the 6-formyl-5,6-dihydro derivatives 65. S The formyl group was transformed into a methyl group by diborane. S The NH group of the dihydro derivatives 64 was acylated by ethyl chloroformate. Reaction with ethyl acrylate and acrylonitrile involved a Michael addition.The ethoxycarbonyl moiety in position 2 and on the side chain in position 6 was hydrolyzed to a carboxylic group by the action of potassium hydroxide in aqueous methanol and was reduced to a hydroxymethyl group by lithium aluminum hydride in ether. 

The 9-hydroxy derivative of the pyrroloquinazoline of type 66 was 0-al-kylated with epibromohydrin, and the epoxy ring was opened with isopropylamine in a pressure bottle under heating.Reaction of 7-hydroxy-2-methylpyrrolo[l,2-c]quinazolin-5(6ff)-one (72) with epibromohydrin in the presence of sodium hydroxide gave the condensed oxazine derivative 73. ... 

The only example of this new class of reaction is the conversion of imines of Af-(2-trifluoracetylphenyl)pyrrolidines to diastereomerically pure pyrroloquinazolines by heating in butanol for 5 days (Scheme 28) (84TL4309). 

Transformation of heterocycles has also been used to synthesize condensed nitrogen heterocycles. So A-tosylaziridine has been treated with two mol 10 to yield two different bis-adducts depending on the reaction temperature. At 100 °C pyrrolopyridine 91 was formed, while reaction at 10 °C afforded the spiro compound 92. Condensation of 10 with chloroacetanilides did not only yield pyrrole derivatives like 28 but also pyrroloquinazolines... 

The crystal and molecular structures of (-)-28 hydrochloride have been determined by X-ray crystallography ( )-28 possesses the R configuration at C-3, and the pyrrolidine ring is in the envelope conformation (67). C-NMR spectra of 28, vasicinone (29), and related compounds have been reported (68), and the mass spectral fragmentations of 28, vasicinone (29), deoxyvasicine (32), and deoxyvasicinone (33) (Fig. 2) have been discussed (69,70). The mass spectral behavior of 2,3-polymethylene-3,4-dihydroquinazolin-4-ones (71) and of 2,3-polymethylene-1,2,3,4-tetrahydroquinazolin-4-ones (72) have been studied. Integrated intensities of the 1480-1630-cm IR bands of the skeletal vibrations of the heteroaromatic rings of pyrroloquinazoline alkaloids have been correlated with electron densities and substituent effects (73). 

Pegamine (8) may be a potential intermediate for deoxyvasicinone (33). Ad-hatodine (43), vasicoline (41), vasicolinone (42), anisotine (35), and sessiflorine (38) may arise from pyrroloquinazolines and derivatives of anthranilic acid. 

The numbering of the pyrroloquinazoline ring system is a source of some confusion. Spath (198), Yunusov et al. (208), Arndt et al. (9), and other workers (e. g. 58) have numbered this ring system in different ways. The nomenclature used in this chapter is that used in Chemical Abstracts compounds are listed in Chart 2. 

Distribution of Pyrroloquinazoline Alkaloids Biological Activity Quinazolinocarboline Alkaloids Quinoline, Furoquinoline, Acridone, and 4-Quinoline Alkaloids... 

In addition to the relatively simple anthranilic-derived metabolites mentioned above, several distinctive types of alkaloids are derived from this amino acid. Most of these are associated with the Rutaceae and related families of the Rutales. Among these groups of alkaloids are the quinazoline, pyrroloquinazoline, quinazolinocarboline, quinoline, furoquinoline, and acridone types. 

Fig. 31.4. Selected pyrroloquinazoline alkaloids and the biogenesis of vasicine (modified from Johne, 1986 used with pennission of the copyright owner. Academic Press, Orlando, FL).

Pyrroloquinazoline alkaloids have been reported from the Acanthaceae (Adhatoda vasica, Anisotes), Araliaceae Mackinlaya), Fabaceae (Galega), Malvaceae Sida), Scro-phulariaceae (Linaria), and Zygophyllaceae Peganum) (Johne, 1986). 

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