Our group has maintained a productive collaboration with Dr. Alexandros Makriyannis, the director of the Center for Drug Discovery at Northeastern University, in the area of classical-nonclassical hybrid cannabinoids for mapping the CB1 and CB2 receptors. Over the years we have developed very efficient methods for the asymmetric synthesis of the tricyclic cannabinoids functionalized with reactive groups (azide, isothiocyanate, nitrate ester) for covalent labeling of the receptors. The chemistry in this project is more challenging than the structures might suggest.

More recently our group has been collaborating with Dr. James Turkson, formerly at the University of Hawaii Cancer Center and now at Cedars-Sinai Medical Center in Los Angeles, on the design and synthesis of small molecule inhibitors of STAT3, a protein involved in cell signaling. Aberrantly activated STAT3 promotes tumor development and progression and is found in a number of human cancers including brain, breast and leukemias. This project has led to orally active (in mice) compounds of high potency and good pharmacokinetics.

We are very grateful to have received help from Aloha Green! For more information please see this story.

Recent publications

STAT3 Inhibitors

In collaboration with Dr. James Turkson (Cancer Institute at Cedars-Sinai)
Lead medicinal chemist: Dr. Francisco Lopez-Tapia

Lopez-Tapia, F., Brotherton-Pleiss, C., Yue, P., Murakami, H., Costa Araujo, A. C., Reis dos Santos, B., Ichinotsubo, E., Rabkin, A., Shah, R., Lantz, M., Chen, S., Tius, M. A. and Turkson, J., Linker variation and structure-activity relationship analysis of carboxylic acid-based small molecule STAT3 inhibitors, ACS Med. Chem. Lett. 2018. 9, 250-255
DOI: 10.1021/acsmedchemlett.7b00544

Yue, P., Lopez-Tapia, F., Paladino, D., Li, Y., Chen, C.-H., Namanja, A. T., Hilliard, T., Chen, Y., Tius, M. A. and Turkson, J., Hydroxamic Acid and Benzoic Acid-Based STAT3 Inhibitors Suppress Human Glioma and Breast Cancer Phenotypes In Vitro and In Vivo, Cancer Res.2016. 76, 652-663
DOI: 10.1158/0008-5472.CAN-14-3558

Cannabinoids

In collaboration with Prof. Alexandros Mariyannis (Northeastern University)

Ogawa, G.; Tius, M. A.; Zhou, H.; Nikas, S. P.; Halikhedkar, A.; Mallipeddi, S.; Makriyannis, A., 3′-Functionalized Adamantyl Cannabinoid Receptor Probes. J. Med. Chem. 2015, 58, 7, 3104-3116.
DOI: 10.1021/jm501960u

Dixon, D. D.; Tius, M. A.; Thakur, G. A.; Zhou, H.; Bowman, A. L.; Shukla, V. G.; Peng, Y.; Makriyannis, A. C3-Heteroaroyl cannabinoids as photolabeling ligands for the CB2 cannabinoid receptor. Bioorg. Med. Chem. Lett. 2012, 22, 16, 5322-5325.
DOI: 10.1016/j.bmcl.2012.06.013

Dixon, D. D.; Sethumadhavan, D.; Benneche, T.; Banaag, A. R.; Tius, M. A.; Thakur, G. A.; Bowman, A.; Wood, J. T.; Makriyannis, A., Novel 1′,1′-Chain Substituted Hexahydrocannabinols: 9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist. J. Med. Chem, 2010, 53, 15,, 5656-5666.
DOI: 10.1021/jm100641g