New synthesis of benzo-delta-carbolines, cryptolepines, and their salts: in vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of delta-carbolines, benzo-delta-carbolines, and cryptolepines.
The paper describes, in its first part, a new synthesis of benzo-delta-carbolines, cryptolepines, and their salts. The strategy is based on the association between halogen-dance and hetero-ring cross-coupling. It is fully convergent and regioselective with interesting overall yields from 27% to 70%. A halogen-dance mechanism in quinoline series is also proposed. The formal synthesis of potential antimalarial compounds and the first total synthesis of 11-isopropylcryptolepine are also described. In the second part, cytotoxic activity against mammalian cells and activities against Plasmodium falciparum and Trypanosoma cruzi of benzo-delta-carbolines and delta-carbolines were evaluated in vitro to study the structure-activity relationships. For benzo-delta-carbolines, methylation at N-5 increases the cytotoxic and antiparasitic activities. A further alkylation on C-11 generally increases the cytotoxic activity but not the antiparasitic activity, cryptolepine and 11-methylcryptolepine being the most active on both parasites. Taking advantage of the fluorescence of the indoloquinoline chromophore, cryptolepine was localized by fluorescence microscopy in parasite DNA-containing structures suggesting that these compounds act through interaction with parasite DNA as proposed for cryptolepine on melanoma cells. For delta-carbolines, methylation at N-1 is essential for the antimalarial activity. 1-Methyl-delta-carboline specifically accumulates in the intracellular parasite. It has weak cytotoxic activity and can be considered as a potential antimalarial compound.
Arzel
E
E
Institut National des Sciences Appliquées, UMR 6014, BP 08, 76131 Mont-Saint-Aignan Cedex, France.
Rocca
P
P
Grellier
P
P
Labaeïd
M
M
Frappier
F
F
Guéritte
F
F
Gaspard
C
C
Marsais
F
F
Godard
A
A
Quéguiner
G
G
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D016054:DNA, Protozoan / Q000737:chemistry; D006801:Humans; D026121:Indole Alkaloids; D007211:Indoles; D008856:Microscopy, Fluorescence; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects
D000470:Alkaloids; D000962:Antimalarials; D000970:Antineoplastic Agents; D002243:Carbolines; D016054:DNA, Protozoan; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; D014344:Trypanocidal Agents; C024015:cryptolepine