Synthesis of Centratherin indole derivatives

Sesquiterpenoids lactones are recognized as biologically active compounds exhibiting antimicrobial, cytotoxic, antitumoral and anti-inflammatory behavior. Centratherin, a sesquiterpenoid lactone, belongs to the furanoheliangolide group and was isolated from Eremanthus Crotonoides found in Brazilian restinga. This natural product is highly bioactive against glioblastoma cell lines U251 and U87-MG, showing IC50 values slightly lower comparing with Doxorubicin.
The structural diversity found in natural products inspires synthetic and medicinal chemists as templates for rational modifications, often based on the insertion of pharmacophore subunits, leading to new hybrid architectures, allowing for the discovery of new bioactive candidates. In this context, the privileged indole scaffold presents itself as a versatile building block due to its wide spectrum of biological activities. Indoles can be found in alkaloids, amino acids, hormones, marketed drugs and clinical trial candidates, possessing more than 30 different activities.
In this work we present the synthesis of a series of Centratherin derivatives by insertion of a chiral indole side chain through an ester linkage, aiming for new bioactive derivatives against tumor cell lines. The synthesis of these analogs has 3 steps, starting with the enantioselective organocatalytic indole alkylation between indoles 1 and (E)-cinnamaldehyde (2) in the presence of organocatalysts 3 and 4 to furnish the chiral aldehydes 5a-b in good yields and high ee’s. Subsequently, the carboxylic acids 6a-b were obtained under Pinnick oxidation conditions and submitted to a Steglich esterification reaction with Centratherin giving the desired analogs 7a-b.
In conclusion, we have provided the synthesis of new 8 diastereisomeric Centratherin analogs. After fully characterized, we intend to evaluate their biological activities against tumor cell lines seeking for new biologically active compounds for cancer treatment.