Pyrrole Bioactive pyrroles

The wide latitude of structural variation consistent with bioactivity in this series is illustrated by the observation that antiinflammatory activity is maintained even when the second aromatic group is attached directly to the pyrrole nitrogen rather than to the heterocyclic ring via a carbonyl group as in the previous case. Condensation of p-chloroaniline with hexane-2,5-dione (or its dimethoxy-tetrahydrofuran equivalent) affords pyrrole 7. The acetic acid side chain is then elaborated as above. Thus, Mannich reaction leads to the dimethylaminomethyl derivative 8, which is in turn methylated (9) the quaternary nitrogen replaced by cyanide to afford 10. Hydrolysis of the nitrile then gives clopirac (11). 

The Cacchi group [85] developed a Pd-catalyzed domino process between o-alky-nyltrifluoroacetanilides as 6-157 and aryl or alkenyl halides, which leads to substituted pyrroles within an indole system. This scheme was successfully applied to the preparation of indolo[2,3-a]carbazoles as 6-158 using N-benzyl-3,4-dibro-momaleimide (Scheme 6/1.42). The indolocarbazole is found in several bioactive natural products as arcyriaflavin A and the cytotoxic rebeccamycin. 

This provides a simple route to difficult-to-obtain compounds of the 4,5-dihydrobenzo[g]indole series, which are rather promising in the search for new bioactive substances and dyes. 4,5-Dihydrobenzo[g]indole (see Table XIX) was isolated by column chromatography (A1203, Et20/hexane 1 2) as colorless crystals that turn blue in air. The H-NMR spectrum of pyrrole 36 (CDCI3, ppm) shows 7.1 m (four benzene protons) 6.8 t and 6.0 t (two pyrrole protons) and 2.8 m (four protons in positions 4 and 5). The IR spectrum shows the characteristic bands of the pyrrole and benzene moieties (cm-1) 695, 730, 765, 1510, 1560, 1580, 1610, 3040, 3050, 3100, 3390, and 3430. 

Tsukamoto S, Tane K, Ohta T, Matsunaga S, Fusetani N, van Soest RWM (2001) Four New Bioactive Pyrrole-Derived Alkaloids from the Marine Sponge Axinella brevistyla. J Nat Prod 64 1576... 

The various substituents (R) of glucosinolate (R-glucosinolate) compounds include alkyl, hydroxyalkyl, aryl (e.g. Phe-CH2, jft-HO-Phe, Phe-(CH2)2), indol-3-yl (Phe pyrrole), methylsulfonyl alkyl (GH3—S02—(GH2) ), methylsulfinylalkyl (GH3—SO—(CH2) ) and methylthioalkyl (CH3—S—(CH2) ) groups. These give rise to the corresponding isothiocyanates (R—N=C=S) that can have particular bioactivities such as insect attractant, insect deterrent, cytotoxic, lachrymatory, tastant and odorant activities. 

Two syntheses of pseudoceratidine (120), which was reported to inhibit metamorphosis of the barnacle Balanus amphitrite, have been described [146,147]. To delineate the structural requirements for this bioactivity, the corresponding N-1 and N-8 mono-(4,5-dibromo-2-pyrrolyl) amides of spermidine were also synthesized, as well as the closely related mono- and bis-(4,5-dibromo-2-pyrrolecarboxamido) residues to test the importance of the pyrrole substituents and the positively charged secondary amine group in 120 [148]. 

A brominated pyrrole-imidazole alkaloid, rac-dibromophakellstatin, has been shown to display selective antitumor activity in vitro with the highest activity on the ovarian cancer cell line OVXF 899L <2007BMCL346>. The chemistry and bioactivity of anti-tubulin agents, either natural or synthetic, having an indole as core nucleus have been reviewed <2007MI209>. 

Marine sponges produce a wide range of alkaloids with potent bioactivities, which include such specific classes as 3-alkylpiperidine, guanidine, indole, polyamine, pyridoacridine, and pyrrole-imidazole alkaloids. Their biological activities vary from antimicrobial to neurological. 

Pyrrole derivatives are important intermediates in the synthesis of bioactive porphyrins [108]. Octaethylporphyrin (OEP), for example, is widely used for biological modeling studies because of its high symmetry, relatively good solubility, and stability. Pyrrole derivatives are also important intermediates for the synthesis of bile pigments, drugs and agrochemicals. 

Recent research progresses on lamellarins and analogous hexacyclic polyaromatic pyrrole alkaloids of bioactive marine mollusk 05CJO641. 

Just as in life, five-membered heterocycles are of utmost importance to drug discovery. The most conspicuous of all is probably atorvastatin (Lipitor), an HMG-CoA inhibitor. Another bioactive pyrrole shown below is an antipsychotic agent. 

In this chapter, the structures, the source, and bioactivity of selected classes of typical marine alkaloids are described. The emphasis is on compounds that have emerged as novel leads, such as lamellarins (pyrroles), cephalostatins/ritterazines (pyrazines) and ecteinascidins (isoquinolines), and manzamines (P-carbolines) to give relevance to the role of marine alkaloids as an important source of leads for drug discovery. 

Tsukamoto, S., Tane, K., Ohta, T., Matsunaga, S., Fusetani, N., van Soest, R. W. M., (2001). Four new bioactive pyrrole-derived alkaloids from the marine sponge Axinella brevistyla. J. Nat. Prod. 64, 1576-1578. 

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