The effect of increased hydrophobicity at position 6 of luteinizing hormone-releasing hormone (LH-RH) has been investigated by the incorporation of a series of 15 very hydrophobic, unnatural D-amino acids at this position. The unnatural amino acids studied can be considered analogues of phenylalanine with carbocyclic aromatic side chains consisting of substituted phenyl (e.g., 2,4,6-trimethylphenyl, p-biphenyl) or polycyclic aromatic (e.g., naphthalene, anthracene) units. When enzymatic resolution (subtilisin Carlsberg) of the most hydrophobic amino acids failed, the racemic amino acids were incorporated, and the diastereomeric LH-RH analogues were resolved by preparative high-performance liquid chromatography. The analogues were synthesized by the solid-phase technique. All of the synthetic compounds were very potent LH-RH superagonists, but [6-(3-(2-naphthyl)-D-alanine)]LH-RH, [6-(3-(2-naphthyl)-D-alanine), 7-(N alpha-methylleucine)]LH-RH and [6-(3-(2,4,6-trimethylphenyl)-D-alanine)]LH-RH appear to be among the most potent LH-RH agonist analogues yet reported when tested in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds [ED50 approximately 7 x 10(-8) g; twice daily in saline]. These analogues are twice as potent as [D-Trp6,ProNHEt9]LH-RH in this assay system (i.e., approximately 200 times the potency of LH-RH).
No abstract
Six general methods for the synthesis of acyclic and cyclic guanidines, of structures 1 and 2 and bearing a variety of substituents, are described. These guanidines may be symmetrical or unsymmetrical, and the substituents they bear provide the basis for further chemical manipulation. The acyclic guanidines are derived from single carbon intermediates, such as 3, 9, 13, and 14, and the appropriately substituted amine. The cyclic guanidines result from the functionalization of a 2-p-toluenesulfonamidopyrimidine which is subsequently hydrogenated. Use of the tosyl as B protecting group reduces the effects of the strongly alkaline guanidine moiety, and its facile removal is achieved with hydrogen fluoride. Detosylation of the tosyl-protected guanidino diester 12 resulted in formation of the imidazolin-4-one 51; this reaction proved to be general for the guanidines 1, 2 = 1, and 2, z = 1, 2. These imidazolinones underwent deuterium exchange for which a mechanism involving the formation of a mesoionic intermediate is proposed.
The 'H NMR spectra showed the H-2 signal at lower field than that of H-8 for purines 1-13, but a crossover of the two proton peaks was observed for the 6-phenoxypurines 14-16. Correlations of 6(H-2) and li(H-8) with substituent constants u,, up, up+ (calcd), F, and R were determined for 1-14, and with Brown's up+ and Taft's U R O and UI for fewer compounds. For correlation with both 6(H-2) and 6(H-8), the up set is the best, yielding correlation coefficients of 0.931 and 0.933, respectively. These ~( H ) -u correlations are impractical for predicting proton chemical shifts of 6-substituted purines. However, they are useful in sorting out the regiospecific effects and proportions of the field and resonance components of the 6-substituent, Le., 65% resonance and 35% field for H-2,44% resonance and 56% field for H-8, as derived from the polynomial equations 2 and 3, respectively. These observations are rationalized by considering contributions of the mesomeric structures a-e. Furthermore, because of the uniquely large resonance and field effects of the phenoxy group, the apparent crossover of H-2 and H-8 in 14-16 can be accounted for in the same manner using structures f and g Coburn et aL2 reported the first linear correlation of the chemical shifts of the 8and 2-hydrogen of eight 6-substituted purines plus purine itself with Brown's up+ and Taft's UR substituent constant, respectively. They also reported3 similar relations for the 13C chemical shifts of carbons 8 and 5 but not for the carbons a t other positions for a variety of 6-and 2,6substituted purines. In the course of our studies4 of the electronic aspects and reactivities of purines and pyrimidines, we have examined the relationship between the proton chemical shifts (6(H)) of 16 6-substituted purines and various sets of substituent constants (a). We have found: (1) the ~( H ) -u correlations are impractical for predicting proton chemical shifts of 6-substituted purines; (2) the correlation coefficients ( r ) obtained are useful in sorting out the regiospecific effects and proportions of the field and resonance components of the 6-substituent; and (3) these effects are consistent with certain mesomeric contributions to the purine structure. Results and DiscussionThe chemical shifts of H-2 and H-8 of 16 purine compounds at 0.1-0.2 M in dimethyl sulfoxide are shown in Table I. The 1H NMR peak assignments were made by virtue of partially 8-deuterated samples. The 6-phenoxypurines 14,15, and 16, and trimethylpurin-6-yl ammonium chloride 13 were prepared by nucleophilic substitution of 50% 8-deuterated 6-chloropurine (8), whereas other 6-substituted purines were partially deuterated selectively at the 8-position upon heating in D20.5 The relative order of H-8 at high field and H-2 at low field was obtained for purines 1-13, but a crossover of the two proton peaks was shown by the phenoxypurines 14-16.Correlation of the proton chemical shifts with the substituent constants was accomplished by means of the regression equationThe lH NMR chemical shift 6(H) reflect...
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