Anticancer compoundsCancer is the second leading cause of death by desease in the USA and many European countries. More than 90% of all malignancies are solid tumors, which are hardly sensitive to any therapeutic regimen when diagnosed in an advanced or already metastatic stage. Under these circumstances the discovery and development of novel cancer therapeutics which are more effective, have fewer side effects and are beneficiary to patients is highly desireable.
Zentaris AG we focus on the following structural modifications of mitoxantrone to get new structures with potent anticancer activity:
- Replacement of Ring A by an electron deficient ring-system (e.g. pyridine, pyrimidine, pyridazine etc.)
- Replacement of Ring C by an electron surplus ring-sysem (e.g. pyrrole)
The synthesis of a series of compounds with different patterns of substituents led to encouraging results: A group of compounds could be identified with high anticancer activity based on accumulaton in the S-phase of the cell cycle, thus blocking the entry into the mitose-phase.
Anticancer activity based on intercalationEnlargement of the 3-ring nucleus described above to a 4-ring system led to an indazolo isoquinoline core with remarkably high anticancer activity:
Studies at Zentaris AG revealed that this class of drug molecules act by intercalation into DNA thus inducing local structural changes to the DNA strand, such as unwinding of the double helix. These structural modifications lead to functional changes, often to the transcription and the replication processes [Intercalation induces structural distortions; left: unchanged DNA strand; right: DNA strand intercalated at three locations (red areas]:
The natural product, ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole), was isolated in 1959 from the tropical plant, ochrosia elliptica, and its pronounced antitumor activity was discovered a few years later. Since then, a number of even more potent analogs have been developed and have been tested in clinical trials. Elliptinium acetate has already been introduced into the therapy of breast cancer. Therefore, a number of research groups, including ours, is committed to the search for new and superior compounds within this class of agents. Another lead structure for our synthetic efforts is the ellipticine isomer, olivacine (1,5-dimethyl-6H-pyrido[4,3-b]carbazole).
Previous investigations of our group aimed at the modification of the electronic properties of the tetracyclic system, for instance by formal replacement of the two methyl groups by trifluoromethyl groups, using d-fused pyridazines as key intermediates. The latter compounds act as highly reactive aza dienes in [4+2] cycloaddition reactions (inverse-electron-demand Diels-Alder reactions). More recently, a series of 3-aza analogs of the ellipticine/olivacine lead structure were developed, in which the pyridine ring of the alkaloids is formally replaced by a pyridazine unit. This modification was found to lead to compounds with better chemical stability and enhanced solubility properties. A representative of this compound type (an analog of the drug, retelliptine) showed particulatrly high in-vitro and in-vivo antitumor activity, as determined at the NCI (National Cancer Institute, USA).
A hitherto unknown 3-aza-olivacine was synthesized recently, and also this agent showed significant antitumor activity in an in-vitro screening. Further representatives of this group include structures with a pyrimido[5,4-b]carbazole skeleton. A novel type of bridged b-fused carbazoles could be made accessible by us, applying a strategy based on an intramolecular “inverse” Diels-Alder reaction of indolylalkyl-tethered 1,2-diazines. There are still plenty of structural modifications to be explored, and our investigations have been extended to tetra- and pentacyclic imides with structural resemblance to the topoisomerase-II-inhibitor, amonafide. Evaluation of biological activity in the field of antitumor agents was performed by an industrial partner, Zentaris AG (Frankfurt, Germany).
luotonin A, which is known to possess antitumor activity via a biological mechanism related to topoisomerase I. So far, a series of ring-A-modified derivatives of the natural lead structure have been made available via two complementary (orthogonal) pathways, both based on intramolecular [4+2] cycloadditions reactions as the key step.