Camptothecin

Camptothecin (CPT) is a cytotoxic quinoline irinotecan. ^[1][2]

Structure

CPT has a planar pentacyclic ring structure, that includes a (S) configuration (the E-ring. Its planar structure is thought to be one of the most important factors in topoisomerase inhibition.^[3][4]

Binding

CPT binds to the topo I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. This prevents DNA relegation and therefore causes DNA damage which results in apoptosis. CPT binds both to the enzyme and DNA with arginine 364 (Arg364). The D-ring interacts with the +1 pyrimidine ring of +1 cytosine.^[5][6]

Physical and chemical properties

CPT is a hydrolysis, forming carboxylate. The open ring form is inactive and it must therefore by closed to inhibit topo I. The closed form is favored in acidic condition, as it is in many cancer cells microenvironment. CPT is transported in to the cell by lipophilicity, which enhances intracellular accumulation. Lipophilicity makes compounds more stable because of improved lactone partitioning into red blood cells and consequently less hydrolysis of the lactone. CPT has affinity for human serum albumin (HSA), especially the carboxylate form of CPT. Because of that, the interactions could result in improved activity.^[5][7]

SAR – Structure-activity relationship

Studies have shown that substitution at position 7, 9, 10 and 11 can have positive effect on CPT activity and physical properties, e.g. potency and metabolic stability. Enlargement of the lactone ring by one methylene unit also enhances its abilities, as in homocamptothecin. Substitution at position 12 and 14 leads to inactive derivative.^[7]

A- and B-ring modification

Alkyl substitution

Alkyl substitution at position 7 has shown increased cytotoxicity, such as ethylene (C₂H₅) or chloromethyl (CH₂Cl). These groups are able to react with the DNA in the presence of topo I which leads to more tumor activity. It has also been shown that increasing the length of the carbon chain (in position 7) leads to increased lipophilicity and consequently greater potency and stability in human plasma.^[7][5] Other 7-modified CPT analogues are silatecans and karenitecins. They are potent inihibitors on topo I and both have alkylsilyl groups in position 7 which make them lipophilic and more stable. Silatecans or 7-silylcampthothecins have shown reduced drug-HSA interactions which contributes to its blood stability and they can also cross the blood brain barrier. DB-67 is a 10-hydroxy derivative and is among the most active silatecans. BNP1350 which belongs to the series of karenitecins exhibits cytotoxic activity and ability to overcome drug resistance. Still another route to make CPT’s lipophilic is to introduce lipophilic substituents, such as iminomethyl or oxyiminomethyl moieties. One of the most potent compounds is the oxyiminomethyl derivative ST1481 that has the advantage to overcome drug resistance caused by transport systems.^[7] Basic nitrogen in a carbon chain at position 7 makes the compound more hydrophilic and hence more water-soluble. For example is a derivate called CKD-602, which is a potent topo I inhibitor and successfully overcomes the poor water solubility and toxicity seen with CPT.^[7][8]

Considerably greater activity can be achieved by putting electron-withdrawing groups like amino, chloro at position 9 and 10 and hydroxyl group at position 10 or 11. But these compounds are relatively insoluble in aqueous solutions, which causes difficulty in administrations. Methoxy group at both position 10 and 11 simultaneously leads to inactivity.^[3][7]

Hexacyclic CPT analogues

Hexacyclic CPT analogues have shown great potency. For example methylenedioxy or ethylenedioxy group connected between 10 and 11 form a 5 or 6 membered ring which leads to more water-soluble derivates and increased potency. Researches have shown that ethylenedioxy analogues are less potent than methylenedioxy. The reason is the unfavourable steric interactions of ethylenedioxy analogues with the enzyme.^[3][7]

Adding amino or chloro group at 9th position or chloromethyl group at 7th position to these 10, 11-methylenedioxy or ethylenedioxy analogues results in compounds with even greater cytotoxicity but weaker solubility in water. To yield 10, 11-methylenedioxy or ethylenedioxy analogues with good water solubility a good way is to introduce a water solubilising substitutent at position 7. Lurtotecan meets those requirements; it’s a 10, 11-ethylenedioxy analogue with a 4-methylpiperazino-methylene at position 7 and has shown a great potency in clinical researches.^[3]

A ring can also be formed between position 7 and 9, like position 10 and 11. That gives new opportunities to make water-soluble derivatives [5]. These hexacyclic CPT become more active when electron-withdrawing groups are put in position 11 and methyl or amino groups at 10. Exatecan is an example of hexacyclic CPT that has a 6 membered ring over position 7 and 9, and is 10-methyl, 11-fluoro substituted [4]. It is water-soluble and more potent than topotecan.^[3][7][9]

C- and D-ring modification

The D- and C-rings have an essential role in the antitumor activity. Replacement in any position results in much less potent compound than parent compound in other cytotoxicity assay.^[3]

E-ring modifications

The E-ring doesn’t allow many structural changes without losing CPT activity. One possible replacement is changing the hydroxyl group to Cl, F or Br because their polarizability is sufficient to stabilize the enzyme-complex.^[7]

Another possible modification is to insert a methylene between hydroxyl and lactone on the E-ring yielding a seven membered β-hydroxylactone group, so-called homocamptothecin (hCPT). The hCPT’s hydroxyl has less protein binding and more affinity for red blood cells than CPT.^[3][7]

CPT analogues

Since the discovery of CPT many analogues have been synthesized. Below is a schematic view of the CPT analogues that have been mentioned in the text above.

References

1. ^ M.E. Wall, M.C.Wani, C.E. Cook, K.H.Palmer, A.I.McPhail, G.A.Sim (1966). "Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate". J. Am. Chem. Soc 88: 3888-3890.
2. ^ G. Samuelsson (2004). Drugs of Natural Origin: a Textbook of Pharmacognosy, 5. 
3. ^ ^{a b c d e f g} H. Ulukan, P.W. Swaan (2002). "Camptothecins, a review of their chemotherapeutical potential". Drugs 62 (2): 2039-2057.
4. ^ A. J. Lu, Z. S. Zheng, H. J. Zou, X. M. Luo, H. L. Jiang (2007). "3D-QSAR study of 20 (S)-camptothecin analogs". European Journal of Medicinal Chemistry 42 (4): 307-314.
5. ^ ^{a b c} D. J. Adams, M. L. Wahl, J. L. Flowers, B. Sen, M. Colvin, M. W. Dewhirst, G. Manikumar, M. C. Wani (2005). "Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient". Cancer Chemotherapy and Pharmacology 57 (2): 145-154.
6. ^ M. R. Redinbo, L. Stewart, P. Kuhn, J. J. Champoux, W. G. J. Hol (1998). "Crystal structure of human topoisomerase I in covalent and noncovalent complexes with DNA". Science 279: 1504-1513.
7. ^ ^{a b c d e f g h i j} F. Zunino, S. Dallavalle, D. Laccabue, G. Beretta, L. Merlini, G. Pratesi (2002). "Current status an perspectives in the Development of Camptothecins". Current Pharmaceutical Design 8: 2505-2520.
8. ^ M. K. Chung, S. S. Han, J. C. Kim (2006). "Evaluation of the toxic potentials of a new camptothecin anticancer agent CKD-602 on fertility and early embryonic development in rats". Regulatory Toxicology and Pharmacology 45 (3): 273-281.
9. ^ M. Palumbo, C. Sissi, B. Gatto, S. Moro, G. Zagotto (2001). "Quantitation of camptothecin and related compounds". J. Chromatofr. B. Biomed. Sci. Appl. 764 (1-2): 121-40.