Indole analogues

SCHEME 7.20 Cyclopent[6]indole analogues. Quinone methide structure shown with internal hydrogen bonding. 

The indole analogue GR 65630 (34) has been used as a radioactive ligand in studies of binding of various 5-HT3 receptor agonists and antagonists [28],... 

Substituted furo[3,2- ]pyridines are under investigation for use as 5-HTip receptor agonists since indole analogues are known in this application. Compound 152 may have potential as a therapeutic agent for treating migraine <2004BML167>. 

EXTENSIONS AND COMMENTARY In the 1960 s there was quite a bit of interest in a couple of pharmaceutical houses with the indole analogues of amphetamine. Both the alpha-methylated tryptamine (this compound, a-MT) and the alpha-ethylated homologue (a-ET, see its separate recipe) were found to be effective monoamine oxidase inhibitors, and both were clinically studied as potential antidepressants. The ethyl compound became a commercial drug, offered by the Upjohn Company as Monase, but now is considered to be without medical use and is a Schedule I drug. It is interesting that this methyl compound, a-MT was also a medically available antidepressant in the Soviet Union in the 1960 s and was sold under the name of Indopan, in 5 and 10 milligram tablets. 

Rezaie and Bremner reported the synthesis of tricyclic 1,4-thiazepines by ring contraction. OT-Cyclophane lactam 237 was treated with Ar-bromosuccinimide and azoisobutyronitrile to yield 47% of dihydroindole derivative 238, as the major product next to side products 239-242 (Scheme 42). The same reaction condition was applied for the ester derivative of 237 (X = COOCH3>, but with longer reaction time. This resulted in indole analogues 240-242 (X = COOCH3) without the formation of dihydroindole derivatives. Bromination on the aromatic ring was observed prior to the intramolecular cyclization. The exact mechanism has not been resolved, but a possible reaction sequence could be... 

The 13C spectrum of emetine (112) (Fig. 23 and Table XXII) was examined by Wenkert and co-workers (69). The chemical shift assignments were made by comparison with the shifts recorded for the simple isoquinolines and pro-toberberine alkaloids such as tetrahydropalmatine (69) (6, 14), and with indolic analogues of emetine (69). The shifts of C-4 and C-6 are characteristic of a trans-quinolizidine conformation for this ring system by analogy... 

Some years ago a benzothiophene that exhibited some activity as a tubulin polymerization inhibitor and appeared to bind weakly to the colchicine binding domain of tubulin was reported. This finding stimulated the synthesis of several benzofuran and indole analogues, Fig. (17). 

Benzo[b]furan and indole analogues of some recently identified benzo[b]thiophene inhibitors of tubulin polymerization have been synthesized, and their biological activity has been investigated. Among them, the compound 2-(3-hydroxy,4-methoxyphenyl),3-(3,4,5-trimethoxybenzoyl)-6-methoxyfuran-2-one 81 was the most active, exhibiting 5 times the level of potency of Combretastatin A-4. However, it is less potent than Combretastatin A-4 as inhibitor of [3H]colchicine... 

In 1996, the same group 87) reported further work on the synthesis of indole analogues of the cephalotaxine ring system (Scheme 52). The key intermediate in this ring-expansion approach, bromoiminium ion 300, was prepared in three steps from tryptamine and the chloro diester 298 via enamine 299. On treatment with several bases, the iminium ion 300 underwent rearrangement, presumably via the intermediate alkoxide 301, to give the azepinone derivative 302, which was reduced with sodium borohydride to a mixture of isomeric alcohols 303. The alcohols 303 underwent rapid intramolecular cyclization when treated with a 95% solution of sulfuric acid to yield pentacyclic ketone 304. 

McMenamy, R. H. The binding of indole analogues to human serum albumin Effects of fatty acids, /. Biol. Chem., 240, 4235, 1965. 

Several L-serine-related amino acids are substrates for the /3-replacement reaction, while indole analogues or derivatives of indole or a variety of alkanethiols can act as nucleophiles. TRPS also catalyzes /3-elimination reactions with L-serine and with 6-chloro-L-alanine, in which the aminoacrylate is hydrolyzed to pyruvic acid and ammonia. Although the /3-subunit of TRPS catalyzes both types of reaction, subunit association reduces the /3-elimination reaction rate of the complex. ... 

The major metabolite of Penicillium italicum Wehmer, which causes the familiar blue mould on citrus fruits, is deoxybrevianamide E (25) a minor metabolite was shown to be 12,13-dehydrodeoxybrevianamide E, and a third metabolite is suspected to be (26), i.e. the indole analogue of austamide, although direct comparison with authentic material was not possible. 

Diarylindoles, e.g. (7), classified as heterocombretastatins with respect to the ethylene bridged diaryl structure and the 3,4,5-trimethoxy substitution pattern, displayed cytotoxicity especially towards leukaemia, non-small cell lung and CNS cancers [33, 43]. A modification of the tubulin inhibitor (8) [44] led to the thiophene and indole analogue (9) with remaining high cytotoxicity (ICso-values in the range of 10 to 100 nM) [45]. The structure of (9) also represents a fragment of the tetracyclic tubulin inhibitor (10) [46] that showed similar activity. 

Aryl-4,6-dimethoxybenzofuran (150), an ambident nucleophile, in contrast to its indole analogue, which undergoes an uncontrolled reaction with formaldehyde and acid [89CC425], reacts smoothly with formaldehyde to afford both symmetrically linked 2,7 2,7 2,7- and unsymmetrically linked 2,2 7,7 2,7- calix[3]-benzofurans 152 and 153 (R = Ar, R = H) in moderate yields (99T4803). However, 151 with formaldehyde formed calix[4]benzofuran derivative 154 (R = Bu, R = H) but with dimethoxymethane and acetic acid afforded the corresponding 152 and 153. 

Although I do not cover the synthesis of indolines, oxin-doles, isatins, and azaindoles in this monograph, some excellent reviews on the synthesis of these indole analogues are available [241-243],... 

Instead of allyl bromide derivative, vinyl diazoacetate in the presence of rhodium acetate also allowed the formation of substituted indolines in excellent yields (Scheme 9.34). N-deprotonated allyl thionium was postulated as intermediate [157], no reaction being observed with an N-methyl indole analogue. 

MedebieUe M, Fuji S, Kato K (2000) An electrochemical approach for the synthesis of perfluroalkylated purine and indole analogues of plant growth regulators. Tetrahedon 56 2655-2664... 

---