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| Formula | C20H16N2O4 |
| Molar mass | 348.358 g·mol−1 |
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| Melting point | 275 to 277 °C (527 to 531 °F) |
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Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark of Camptotheca acuminata (喜树 "Happy tree"), a tree native to China used in traditional Chinese medicine.[1][2] It has been used clinically in China for the treatment of gastrointestinal tumors.[3] CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers.[4] However, it has low solubility and adverse effects have been reported when used therapeutically,[3] so synthetic and medicinal chemists have developed numerous syntheses of camptothecin[5][6][7] and various derivatives to increase the benefits of the chemical, with good results. Four CPT analogues have been approved and are used in cancer chemotherapy[8] today: topotecan, irinotecan, belotecan, and trastuzumab deruxtecan.[9][10] Camptothecin has also been found in other plants including Chonemorpha fragrans.[11]
Structures
[edit]CPT has a planar pentacyclic ring structure, that includes a pyrrolo[3,4-β]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring). Its planar structure is thought to be one of the most important factors in topoisomerase inhibition.[12][13]
Natural Sources
[edit]Although CPT was first isolated from the bark of C. acuminata, it has been found in many other angiosperm as well, some of which are unrelated species.[14]
| Order | Family | Species |
|---|---|---|
| Cornales | Nyssaceae | Camptotheca acuminata |
| Camptotheca lowreyana S.Y.Li | ||
| Camptotheca yunnanensis Dode | ||
| Gentianales | Rubiaceae | Ophiorrhiza pumila |
| Ixora coccinea L. | ||
| Ophiorrhiza. alata Craib | ||
| Ophiorrhiza rugosa var. decumbens (Gardner ex
Thwaites) Deb & Mondal | ||
| Ophiorrhiza rugosa var. prostrata (D.Don) Deb & Mondal | ||
| Ophiorrhiza filistipula Miq. | ||
| Ophiorrhiza mungos L. | ||
| Ophiorrhiza mungos L. var. angustifolia (Thw.) Hook. f. | ||
| Ophiorrhiza grandiflora Wight | ||
| Ophiorrhiza shendurunii A.E.S.Khan, E.S.S.Kumar
& Pushp. | ||
| Ophiorrhiza pectinata Arn. | ||
| Ophiorrhiza trichocarpa Blume | ||
| Ophiorrhiza japonica Blume | ||
| Apocyanaceae | Ervatamia heyneana | |
| Chonemorpha grandiflora G.Don | ||
| Tabernaemontana alternifolia L. | ||
| Gelsemiaceae | Mostuea brunonis | |
| Celastrales | Icacinaceae | Merrilliodendron megacarpum |
| Nothapodytes foetida | ||
| Pyrenacantha klaineana | ||
| Mappia pittosporoides Oliv. | ||
| Nothapodytes nimmoniana | ||
| Merrilliodendron megacarpum (Hemsl.) Sleumer | ||
| M. dentata | ||
| Pyrenacantha klaineana Pierre ex Exell & Men-
donça | ||
| Loganiaceae | Mostuea brunonis Didr. |
In addition to being found in plants, select endophytes have also been known to produce CPT and have been extensively studied as an alternative source to harvest.[14] These endophytes are often bacteria or fungi that co-exist within plants and have been identified as a source of secondary metabolites such as taxol, capsaicin, rohitukine, as well as CPT.[15] Endophytes can be isolates from plant material such as bark, twigs, leaves, and fruit. For example, three CPT-producing fungi (T. atroviridae LY357, Aspergillus sp. LY341, and Aspergillus sp. LY355) have been isolated from different parts of C. acuminata.[14]
| Name | Family |
|---|---|
| Trichoderma atroviridae LY357 | Hypocreaceae |
| Aspergillus sp. LY341 | Trichocomaceae |
| Aspergillus sp LY355 | |
| Fusarium solani MTCC 9667 | Nectriaceae |
| Fusarium solani MTCC 9668 | |
| Fusarium oxysporum kolhapuriensis | |
| Alternaria alstroemeriae | Pleosporaceae |
| Alternaria burnsii | |
| Anthracnose fungus SUK1 (F1) | Glomerellaceae |
| Corynespora cassiicola | Corynesporascaceae |
| Entrophospora infrequens | Acaulosporaceae |
| Fusarium. oxysporum NFX06 | Nectriaceae |
| Neurospora crassa | Sordariaceae |
| Nodulisporium | Xylariaceae |
| Fomitopsis sp. (MTCC 10,177) | Fomitopsidaceae |
| Phomopsis sp | Valsaceae |
| Alternaria alternata (MTCC 5477) | Pleosporaceae |
Binding
[edit]CPT binds to the topoisomerase I and DNA complex (the covalent complex) resulting in a ternary complex, and thereby stabilizing it. This prevents DNA re-ligation and therefore causes DNA damage which results in apoptosis.[16] CPT binds both to the enzyme and DNA with hydrogen bonds. The most important part of the structure is the E-ring which interacts from three different positions with the enzyme. The hydroxyl group in position 20 forms hydrogen bond to the side chain on aspartic acid number 533 (Asp533) in the enzyme. It is critical that the configuration of the chiral carbon is (S) because (R) is inactive. The lactone is bonded with two hydrogen bonds to the amino groups on arginine 364 (Arg364). The D-ring interacts with the +1 cytosine on non-cleaved strand and stabilizes the topoisomerase I-DNA covalent complex by forming hydrogen bond. This hydrogen bond is between carbonyl group in position 17 on the D-ring and amino group on the pyrimidine ring of +1 cytosine.[17][18] CPT is selectively cytotoxic to the cells replicating DNA during S phase [19] and its toxicity is primarily a result of conversion of single-strand breaks into double-strand breaks when the replication fork collides with the cleavage complexes formed by DNA and CPT.[20]
Chemistry
[edit]The lactone ring in CPT is highly susceptible to hydrolysis. The open ring form is inactive and it must therefore be closed to inhibit topoisomerase I. The closed form is favored in acidic condition, as it is in many cancer cells microenvironment. CPT is transported into the cell by passive diffusion. Cellular uptake is favored 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 equilibrium between the lactone ring and the carboxylate form is driven toward the carboxylate. Reduced drug-HSA interactions could result in improved activity.[17][21]
Structure-activity relationship
[edit]
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 CH
2 unit also enhances its abilities, as in homocamptothecin. Substitution at position 12 and 14 leads to inactive derivative.[21]
A- and B-ring modification
[edit]Alkyl substitution
[edit]Alkyl substitution at position 7 has shown increased cytotoxicity, such as ethyl (C2H5) or chloromethyl (CH2Cl). These groups are able to react with the DNA in the presence of topoisomerase 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.[17][21] Other 7-modified CPT analogues are silatecans and karenitecins. They are potent inhibitors on topoisomerase 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.[21] 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 topoisomerase I inhibitor and successfully overcomes the poor water solubility and toxicity seen with CPT.[21][22]
Considerably greater activity can be achieved by putting electron-withdrawing groups like amino, nitro, bromo or 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.[12][21]
Hexacyclic CPT analogues
[edit]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 unfavorable steric interactions of ethylenedioxy analogues with the enzyme.[12][21]
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 substituent 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.[12]
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.[12][21][23]
C- and D-ring modification
[edit]The C- and D-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.[12]
E-ring modifications
[edit]The E-ring doesn't allow many structural changes without losing CPT activity because it is necessary for binding to the active site of TOP I.[24] One possible replacement is changing the hydroxyl group to Cl, F or Br because their polarizability is sufficient to stabilize the enzyme-complex.[21]
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 inductive effect on the carboxyl group which makes the lactone very reactive. This enhances the interaction of the free hydroxyl group optimally with topoisomerase I and the covalent complex that forms in its presence are more stable. The E-ring of hCPT opens more slowly and the opening is irreversible. hCPTs exhibit enhanced human plasma stability because of decreased protein binding and more affinity for red blood cells than CPT.[12][21]
CPT analogues
[edit]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.
 | ||||
| Analogue | R1 | R2 | R3 | R4 |
| Topotecan | —H | 
|
—OH | —H |
| Irinotecan (CPT-11) | 
|
—H | 
|
—H |
| Silatecan (DB-67, AR-67) | 
|
—H | —OH | —H |
| Cositecan (BNP-1350) | 
|
—H | —H | —H |
| Exatecan | 
|
—CH3 | —F | |
| Lurtotecan | 
|
—H | 
| |
| Gimatecan (ST1481) | 
|
—H | —H | —H |
| Belotecan (CKD-602) | 
|
—H | —H | —H |
| Rubitecan | —H | 
|
—H | —H |
CPT is linked to a cyclodextrin-based polymer to form the investigational anti-cancer drug CRLX101.[25]
Biosynthesis
[edit]
Like all other monoterpenoid indole-alkaloids, biosynthesis of camptothecin requires production of the strictosidine. Strictosidine is synthesized through condensation reaction between tryptamine from shikimate pathway and secologanin from either mevalonate (MVA) pathway or non-mevalonate pathway (MEP).[26] Strictosidine then undergoes intermolecular cyclization to produce strictosamide, which is converted to camptothecin through a series of oxidation reactions by enzymes that still needs to be resolved.[27]
The shikimate pathway leading to biosynthesis of tryptamine is mostly understood. First, chorismate is converted to anthranilate by the alpha-subunit of anthranilate synthase (ASA). Anthranilate reacts with 5-phosphoribose pyrophosphate to produce 5-phosphoribosylanthranilate. Then this intermediate is converted to indole glycerol phosphate, which interacts with the alpha-subunit of tryptophan (TSA) synthase to yield indole. The beta-subunit of tryptophan synthase (TSB) catalyzes condensation of indole with serine, leading to tryptophan. In the next step, tryptamine is produced as the result of decarboxylation by tryptophan decarboxylase (TDC).[28]
Secologanin synthesis begins with condensation reaction between pyruvate and D-Glyceraldehyde-3-phosphate catalyzed by 1-deoxy-D-xylulose-5-phosphate synthase (DXS) to produce 1-deoxy-D-xylulose-5-phosphate (DXP). The conversion of DXP to isopentenyl diphosphate (IPP), which is the common terpenoid biosynthesis precursor involves 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) and 1-hydroxy-2-methyl-2(E)-butenyl-4-diphosphate reductase (HDR). The formation of IPP can be achieved by both MVA and MEP pathways.[28] Condensation of IPP and dimethylallyl diphosphate (DMAPP) yields geranyl diphosphate (GPP). The geraniol synthase (GS) then converts GPP to geraniol.[26] The conversion of geraniol to secologanin occurs through various enzymatic reactions. Based on studies with radioactive labelling and pathway specific inhibitors, MEP pathway is the primary source for secologanin.[28] Tryptamine from shikimate pathway and secologanin from MVA or MEP pathway are converted to strictosidine through a condensation reaction catalyzed by strictosidine synthase. Although it is not fully resolved, it has been postulated that camptothecin is produced from strictosidine via strictosamide, 3 (S)-pumiloside and 3 (S)-deoxypumiloside.[27]
Synthetic CPT Production
[edit]One of the main challenges with mass producing synthetic CPT is the inability to be purified with column chromatography, high production costs, low yield, and toxic reagents. By overcoming these problems, the production of CPT can be scaled to levels necessary for industrial drug development. Previously, different 9 and 10 step syntheses have been developed to produce CPT along with a 6 step procedure that produced a racemic CPT mixture.[29] However an enantiopure final product is desired for drug design and so a viable synthetic pathway to do so has been extremely sought after. The 6 step synthesis below can be used for the production of (S)-camptothecin and only relies on two starting materials A and B, both of which can be made from readily available commercial reagents: 2-methoxypyridine and 2-chloro-3-quinolinecarboxaldehyde (both of which are heterocyclic).[30]
Compound A can initially be created from reacting commercially available 2-methoxypyridine. First it is lithiated at carbon 3 and treated with N-formyl-N, N', N' -trimethylethlenediamine to give an R-amina alkoxide. From this, a dianion can be formed by further directed lithiation at carbon 4 of the n-BuLi affected R-amino alkoxide. Next, addition of iodine with aqueous NaBH / CeCl produced the alcohol with a yield of 46%. This alcohol could then be converted to compound 7 directly with a relatively high yield of 87%. Finally, compound A can be created in one step via addition of HCl and I-PrOH.[30]
Compound 6 can be made from commercially available starting material quinolinecarboxaldehyde using previously established methods. [31]
Finally, by reacting both compounds A and B using the reagents in the third figure produces enantiopure (S)-camptothecin with a 64% overall yield after recrystallization and purification.[30] Upon further testing, the compound produced by this technique is identical to the natural product in all manners.
Exploring synthetic pathways for CPT production is important not only for viable large-scale production of the molecule itself but also for the development of analogues that may be useful in further research and drug development.
CPT Production via Cell Cultures
[edit]One of the main issues with industrial scale production of CPT is the rapid depletion of natural resources. As opposed to synthetic production, utilizing techniques such as plant tissue or endophyte cultures, this challenge can be overcome. This method requires an explant taken from the mother plant, that is then grown independently of it. By doing so, seasonal limitations present when growing the entire plant can be overcome and metabolites of interest can be isolated and purified easier than if taken directly.
This process occurs in two phases. The first step involves the accumulation of biomass. This is required to build up a sizable culture that can then grow and produce the desired compounds. Next, metabolite synthesis begins and is heavily regulated to maximize the output. Both phases must be optimized to ensure maximal production, which can be done in a variety of ways. By selecting for plants with a genotypes known to have high metabolite production and cells with the least variety in production levels, synthesis can be optimized at a genetic level. Additionally, when choosing cells to culture, those from organs and other differentiated tissues should be favored if possible as metabolite production is often higher in them compared to basal levels. Organs of interest to harvest include roots, shoots, and embryos that have been known to produce the most stable results.[14]
To further ensure the most optimal conditions for the culture to grow, environmental variables can be manipulated after the proper cells have been selected. For maximum growth to promote the most accumulation of biomass, the pH, temperature, light intensity, carbon content, and nitrogen content can be altered to produce the most stable environment. Once biomass accumulation finished, the next phase can also be further enhanced using developed lab techniques. For example, during metabolite production techniques such as elicitation, precursor feeding, and immobilization can be used to encourage higher production levels.[14]
References
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