Molecular hybridization aims to combine two biologically active compounds to form a new bioactive entity. Hybrid compounds may show affinity and efficacy superior to the parent compounds, better pharmacokinetic and pharmacodynamic properties, improved therapeutic index and reduced risk of unwanted side effects. In this research project, we aim to develop merged hybrid tubulin binding agents that are designed by overlapping the pharmacophore moieties of two active drugs and by joining them to obtain a single multiligand entity. These compounds take advantage that being relatively smaller compared to the "true" hybrids can potentially fit better into the colchicine site. Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are frequently used in combination for cancer therapy. We aim to obtain dual targeting microtubule and Top2 merged hybrids to achieve anticancer effects. Our strategy is to merge the ARDAP, ARAP and ATI scaffolds with structural features required for the Top2 inhibition, using YCH337 as a reference compound. The new compounds are expected to elicit inhibition of cancer cells, including the MDR cells, to arrest the cells in mitosis and to induce apoptosis. These compounds should behave differently from the combination of a microtubule inhibitor and a Top2 inhibitor, particularly in inducing apoptosis. To our knowledge, microtubule and carbonic anhydrase merged inhibitors have never been reported so far. We aim to synthesize first in class new inhibitors by including the characteristic pharmacophoric feature of the human carbonic anhydrase inhibitors, the benzensuldonamide moiety, into the ARDAP, ARAP and ATI scaffolds. The agents have potential to be used in the treatment of cancer, as well as in other pathologies, such as retinal and cerebral edema, glaucoma, epilepsy, as well as in preventing acute mountain sickness.
Both microtubules and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors have been widely used for cancer therapy. The dynamic equilibrium between polymerization and depolymerization of microtubules precisely regulates their function (1). Interference with this balance by promoting polymerization or depolymerization disrupts microtubule and thus impairs the mitotic spindle assembly. Consequently, cells are arrested in M phase, causing proliferative inhibition or even cell killing (2). On the other hand, Top2, a nuclear enzyme, is critical for resolving DNA complexity and for segregating chromosomes in mitosis (3). Top2 catalytically cleaves the DNA duplex and mediates the passage of its one segment through another. This process generates transient Top2-DNA covalent complexes (Top2cc) and DNA double-strand breaks (DSB) that are normally rapidly repaired. Stabilizing the Top2cc results in the accumulation of DSB, which activates DNA damage response, subsequently leads to G1, S and/or G2 arrest and induces apoptosis. This is the basic mechanism of action of Top2 poisons (e.g., podophyllotoxins and anthracyclines), the most important subclass of Top2 inhibitors in the clinic (9) (Figure 2).
Microtubule inhibitors and Top2 inhibitors are frequently used in combination for cancer therapy. Many therapeutic regimens contain vincristine, vinblastine, paclitaxel or docetaxel in combination with doxorubicin or etoposide for the treatment of various haematological or solid tumours (5). These combinations have been reported not only to produce synergistic therapeutic effects but also to reduce nonhematologic toxicities (6). However, these drug combinations may lead to treatment failures due to improper combinations and emergence of MDR cross-resistant to both of them.
To our knowledge, few single agents have been reported as yet to concomitantly inhibit microtubule and Top2. In principle, such agents could cause similar therapeutic efficacy as the combination of the two classes of inhibitors but make the drug choice and administration simpler and easier. Moreover, these agents could also overcome MDR and individual drug resistance, thereby achieving more persistent therapeutic effects. We aim to obtain dual targeting microtubule and Top2 merged hybrids to achieve anticancer effects, as exemplified by Figure 3. Our strategy is to merge the ARDAP, ARAP and ATI scaffolds (7) with structural features required for the Top2 inhibition, using YCH337 as a reference compound (8). The new compounds are expected to elicit inhibition of cancer cells, including the MDR cells, to arrest the cells in mitosis and to induce apoptosis. These compounds should behave differently from the combination of a microtubule inhibitor and a Top2 inhibitor, particularly in inducing apoptosis.
To our knowledge, microtubule and carbonic anhydrase merged inhibitors have never been reported so far. We aim to synthesize first in class new inhibitors by including the characteristic pharmacophoric feature of the human carbonic anhydrase inhibitors, the benzensuldonamide moiety (9,10), into the ARDAP, ARAP and ATI scaffolds. The agents have potential to be used in the treatment of cancer, as well as in other pathologies, such as retinal and cerebral edema, glaucoma, epilepsy, as well as in preventing acute mountain sickness.
References
1) Nat. Rev. Cancer 2009, 9, 338-350. 2) Eur. J. Med. Chem. 2014, 87C, 89-124. 3) Annu. Rev. Biochem. 2013, 82, 139-170. 4) Chem. Rev. 2012, 112, 3611-3640. 5) Holland-Frei Cancer Medicine (6th ed) 2003, 2, 1195-2290. 6) Oncologist 2001, 3, 5-12. 7) Eur. J. Pharm. Sci. 2019, 131, 58-68. 8) Oncotarget 2015, 6, 8960-8973. 9) J. Med. Chem. 2015, 58, 8564-8572. 10) ACS Med. Chem. Lett. 2019, 11, 633-637.