(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. 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.
Megati
S
S
Department of Chemistry, Michigan Cancer Foundation, Detroit 48201.
Goren
Z
Z
Silverton
J V
JV
Orlina
J
J
Nishimura
H
H
Shirasaki
T
T
Mitsuya
H
H
Zemlicka
J
J
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003641:Deamination; D015497:HIV-1 / Q000187:drug effects*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C056909:adenallene; D000243:Adenosine Deaminase; D000225:Adenine