N-Ethylcarboxamidoadenosine (12) was synthesised from adenosine (1) and the 6-chloro-2,3-O-isopropylidene-AT-ethylcarboxamidoadenosine (25) was synthesised from inosine (19).
Employing molecular modelling techniques and the results from previous structure activity relationships it was possible to design and synthesise a N6-substituted N-ethylcarboxamidoadenosines which possessed an oxygen in the N6-substituent either in the form of an epoxide (which was obtained by cpoxidising an alkene with m-CPBA or dimethyldioxirane) or in the form of a cyclic ether as was the case for N6-((tetrahydro-2H--pyran--2-yl)methyl-N-ethylcarboxamidoadenosine (78). These compounds were tested for their biological activity at the A1 adenosine receptor by their ability to inhibit cAMP accumulation in DDT, MF2 cells. The EC50 values obtained indicated that the N6-(norborn-5-en-2-yl)-N-ethylcarboxamidoadenosines were the most potent. Of theseN6-(S-endo-norbrn-5-en-2-yI)-N-ethylcarboxaniidoadenosine (56) was the most potent (0.2 nM). N6-(exo-norborn-5-en-2-yl)-2-iodo-N-ethylcarboxamidoadenosine (79) was synthesised from guanosine (22) and was also evaluated for its potency at the A, receptor (24.8 ± 1.5 nM). At present 79 is being evaluated for its selectivity for the A1 receptor compared to the other three receptor subtypes (A2a, A2b, A3). A series of N6-(benzyl)-N-ethylcarboxamidoadenosines were synthesised with substitutions at the 4-position of the phenyl ring. Another series of compounds were
synthesised which replaced the methylene spacer between the N6H and the N6-aromatic
or lipophilic substituent The replacement groups -were carbonyl and trans-2-
cyclopropyl moieties. The N6-acyl compounds were obtained by reacting 2,3-O-
di(tert-butyldimethylsilyl)-AT-ethylcarboxamidoadenosinc (59) with the appropriate acid chloride and then deprotecting with lelrabutylammonium fluoride in
tetrahydrofuran. The compound N6-(4-(1,2-dihydroxy)ethyl)benzyl-N-
ethylcarboxamidoadenosine (125) was synthesised by the reaction of 4-(1,2-0-
isopropylidene-ethyl)benzyl aminc (123) with 6-chloro-2,3-0-isopropylidene-N-
ethylcarboxamidoadenosine (25). Compound 123 was synthesised from an
epoxidation of vinylbenzyl phthalimide (118) followed by an acidic ring opening to
yield the diol which was isopropylidenated to yield 4-(l,2-O-isopropylidene-
elhyl)benzyl phlhalimide (122), It was hoped that the presence of the diol
functionality in 125 would increase water solubility whilst maintaining potency at the
A3 receptor.
| Identifer | oai:union.ndltd.org:ADTP/217063 |
| Date | January 1998 |
| Creators | Wright, Denis Matthew John, mikewood@deakin.edu.au |
| Publisher | Deakin University. School of Biological and Chemical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://www.deakin.edu.au/disclaimer.html), Copyright Denis Matthew John Wright |
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