2008 Cyclosquaramide compounds against cancer and other diseases

The University has developed a new group of macrocyclic squaramide based compounds that have demonstrated their ability to become candidates for anti-tumor agents.

As a result of the multidisciplinary cooperation between researchers from the areas of chemistry and cellular biology of the UIB a new family of chemical compounds, capable of inhibiting in vitro (inhibition >75%) a series of proteins-kinase related to diseases such as cancer, diabetes, neurodegenerative diseases or HIV replication, has been synthetized. The results obtained up to date show that these compounds have an important biological activity and selectivity with regard to some types of cancer, even between those of the same origin.


The rational design of new molecules with specific molecular recognition ability is a strategic field for the development of new therapeutic agents. In this sense, the UIB team has developed a novel group of macrocyclic squaramide based compounds, some of which have shown a great ability to inhibit certain kinases associated with cancer, so being considered as candidates for antitumor agents.

But why these compounds?

Macrocycles due to their cyclic structure constitute one of the most numerous groups of therapeutic agents under investigation in pre-clinic and clinic phases for the treatment of a vast number of diseases. On the other hand, squaramides have the capacity to establish hydrogen bonding interactions analogously to amides. They have been described as bioisosters of the group amide, and successfully introduced in bioactive compounds. In addition, cyclosquaramides can be obtained in multigram scale and the synthetic methodology developed for these compounds allows the introduction of structural diversity with little synthetic effort. Moreover, cyclosquaramides are stable compounds that can be stored during long periods of time without necessity to take special precautions.

Main advantages

  • Stability - The cyclosquaramides are stable compounds that can be stored for long periods of time without the need of taking special precautions
  • Toxicity - It has been demonstrated that the activity of the compounds against primary cells derived from chronic lymphocytic leukemia patients present low toxicity to non-tumor T lymphocytes.
  • High degree of selectivity - In some cancers it has been determined that certain cell lines are sensitive to the compounds and others not. The corresponding compounds noncyclic oligoescuaramídes that lead to cicloescuaramidas do not have biological activity.
  • High cellular permeability
  • ATP-noncompetitive inhibition - It has been determined a noncompetitive inhibition with the ATP for the ABL1 kinase. On the another hand, the slope obtained in the adjustment of the IC50 curves indicates an association of the inhibitor to more than one centre on a cooperative manner


Cyclosquaramides are a type of macrocyclic compounds relatively simple to prepare and the methodology developed for their synthesis allows their obtention in high yields of 80% and in multigram scale. In addition, structural modifications on their macrocyclic framework can be easily made, modulating their activity.

They have an antitumor activity for certain types of tumors and high cellular penetrability that favors their transport until the centers where they must act, resolving one of the main problems of antitumor drug administration.

In addition, the preliminary results indicate that the cyclosquaramides do not act in the active center of the kinases. This mechanism is different. Most of the inhibitors that are either in the market or in phases of advanced development interact in the same centers that the ATP. For this reason, we can presume that cyclosquaramides could have a synergic behavior with other drugs or even constitute a good alternative in the cases that a resistance to habitual drugs may exist.

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