(R)-(-)- and (S)-(+)-Adenallene: synthesis, absolute configuration, enantioselectivity of antiretroviral effect, and enzymic deamination

Synthesis of optically pure (-)- and (+)-adenallene 2 and 3 is described. Racemic adenallene (1a) was subjected to deamination with adenosine deaminase monitored by HPLC using a Chiralcel CA-1 column to give (-)-adenallene (2) and (+)-hypoxallene (4). The latter compound was converted to acetate 5....

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Bibliographic Details
Published in:Journal of medicinal chemistry 1992-10, Vol.35 (22), p.4098-4104
Main Authors: Megati, Sreenivasulu, Goren, Zafrir, Silverton, James V, Orlina, Joel, Nishimura, Hisao, Shirasaki, Takuma, Mitsuya, Hiroaki, Zemlicka, Jiri
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - chemical synthesis
Adenine - chemistry
Adenine - pharmacology
Adenosine Deaminase - metabolism
AIDS/HIV
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Chemistry
Condensed matter: structure, mechanical and thermal properties
Cytopathogenic Effect, Viral - drug effects
Deamination
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
HIV-1 - drug effects
human immunodeficiency virus
Kinetics
Models, Molecular
Molecular Conformation
Organic chemistry
Organic compounds
Physics
Preparations and properties
Stereoisomerism
Structure of solids and liquids
crystallography
Structure of specific crystalline solids
Structure-Activity Relationship
Virus Replication - drug effects
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Summary:Synthesis of optically pure (-)- and (+)-adenallene 2 and 3 is described. Racemic adenallene (1a) was subjected to deamination with adenosine deaminase monitored by HPLC using a Chiralcel CA-1 column to give (-)-adenallene (2) and (+)-hypoxallene (4). The latter compound was converted to acetate 5. The reaction of 5 with trifluoromethanesulfonic anhydride and pyridine followed by ammonolysis furnished acetate 6 or (+)-adenallene (3) depending on the solvent used in the last step. Acetate 5 was smoothly transformed to the 6-chloro derivative 7, but an attempted ammonolysis led only to racemization and decomposition. Single crystal X-ray diffraction established the R-configuration of (-)-enantiomer 2. The latter forms a pseudosymmetric dimer in the lattice with the adenine moiety in an anti-like conformation. The torsional angles of the allenic bonds show departures from 90 degrees (91 and 97 degrees, respectively) and rotameric preference of the hydroxymethyl groups is different in both molecules of the dimer. The R-enantiomer 2 inhibited the replication and cytopathic effect of human immunodeficiency virus (HIV-1) in ATH8 cell culture with an IC50 of 5.8 microM, whereas the S-enantiomer 3 was less active (IC50 > 200 microM). The enantioselectivity of the anti-HIV effect is significantly lower than that of 2',3'-dideoxyadenosine. Kinetics of deamination of R- and S-enantiomers 2 and 3 catalyzed by adenosine deaminase gave the following parameters: Km values of S-form 3 and R-form 2 were 0.41 and 0.52 mM with Vmax being 530 and 18.5 mumol/min, respectively [corrected]. Again,, a much lower level of enantioselectivity of deamination was observed than that of D- and L-adenosine. These results indicate (i) different enantioselectivity of enantiomers 2 and 3 as HIV inhibitors and adenosine deaminase substrates and (ii) both R- and S-enantiomers 2 and 3 can function as nucleoside analogues with varied enantioselectivity for different enzymes or receptors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00100a016