Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

Abstract

Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase–Carbonic Anhydrase Dual-Hybrid Inhibitors

“…Although compound 9 bears the primary sulfonamide moiety, it was ineffective against the main tumor-associated hCA IX, with a K I value over the threshold limit of >10000 nM. In contrast, the inhibitory potency against the second tumor-associated hCA XII was almost the same as that of 7 , with a K I value of 8.4 nM. In agreement with previously published data, both coumarin 15 - and sulfocoumarin 20- based CAIs were ineffective inhibitors against the ubiquitous hCA I and II isoforms ( K I > 10000). Interestingly, the switch to the heterocyclic CAI warhead, as in 15 and 20 , resulted in an opposite selectivity for hCAs VA and VB, with a near-full retention of the magnitude (i.e., compound 15 was 2.8-fold more effective against hCA VA than VB, whereas compound 20 was a 3.2-fold more potent inhibitor of hCA VB than VA).…”

“…In agreement with previously published data, both coumarin 15 - and sulfocoumarin 20- based CAIs were ineffective inhibitors against the ubiquitous hCA I and II isoforms ( K I > 10000). Interestingly, the switch to the heterocyclic CAI warhead, as in 15 and 20 , resulted in an opposite selectivity for hCAs VA and VB, with a near-full retention of the magnitude (i.e., compound 15 was 2.8-fold more effective against hCA VA than VB, whereas compound 20 was a 3.2-fold more potent inhibitor of hCA VB than VA).…”

“…A very promising approach to overcome the above-mentioned drawbacks is the development or synthesis of compounds endowed with polypharmacological properties that are thus able to effectively interfere with multiple essential factors in carcinogenesis and metastasis. The dual blockades of PD-L1/MEK and topoisomerase I/HDACs are the best examples to date. We believe that such a strategy is also applicable to hTL and the tumor-associated carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII by means of ad hoc -designed compounds endowed with remarkable inhibitory features on both enzymes (TI-CAIs; structures in Table S1).…”

Penetration into Cancer Cells via Clathrin-Dependent Mechanism Allows L-Asparaginase from Rhodospirillum rubrum to Inhibit Telomerase

“…A very promising strategy for antitumor drug development is a development/synthesis of compounds that have dual activity and can inhibit more than one vital factor in cancer cells. In this regard, dual blockade of PD-L1 and MEK [ 16 ] or hybrid topoisomerase I and HDAC inhibitors have been developed as dual action anticancer agents [ 17 ]. Telomerase remains an attractive target for dual-blockade strategies, and several azidothymidines “clicked” into 1,2,3-triazoles were first reported to be carbonic anhydrase-telomerase dual-hybrid inhibitors [ 18 ].…”

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

“…In inhibition assays, compound 7 was observed to impair the activity of both HDACs and topoisomerase II at similar levels as vorinostat and daunorubicin, respectively [ 262 ]. Following this work, alternative structures based on the camptothecin, acridine and podophyllotoxin scaffolds have been reported [ 253 , 262 , 263 , 264 , 265 ].…”