Cytarabine besides known as ( Ara-C ) is an endovenous chemotherapeutic drug normally used to handle acute myelocytic leukaemia. [ 1 ] This is a malignant neoplastic disease situated on the myeloid line of blood cells, characterised by the rapid growing of unnatural white blood cells that accumulate in the bone marrow.
Ara-C onslaughts both cancerous and non-cancerous cells as they undergo DNA synthesis. [ 1 ] The mechanism of action of each drug is multifaceted but chiefly involves suppressing DNA synthesis. Ara-C is transported into the cell where it is activated by phosphorylation. [ 2 ]
Deoxyribonucleic acid reproduction occurs at the taking strand of the reproduction fork by add-on of the bases in the 5? — & A ; gt ; 3? way to organize one new girl strand. The 2nd girl strand consequences from reproduction of the lagging Deoxyribonucleic acid strand at the reproduction fork where the lagging strand replicates discontinuously and requires synthesis of a primer. Okazaki fragments are intermediates created from the lagging strand as a consequence.
The rate of reproduction for atomic DNA is frequently elevated in malignant cells, peculiarly in aggressive tumors, comparative to environing healthy tissues. [ 3 ] Disruption of DNA reproduction of malignant cells inhibits tumour growing and enlargement. Therefore interrupting DNA synthesis preferentially targets malignant cells. Ara-C feats this mechanism to stamp down tumour growing. Ara-C can make this because it is an parallel of cytidine and becomes misincorporated into DNA during reproduction alternatively of cytidine doing changes in the construction, stableness and protein adhering features of the girl DNA.
Cytarabine inhibits DNA elongation, with suppression happening preponderantly at the lagging strand of the reproduction fork. [ 3 ] It is besides an S-phase-specific agent upon activation and is a competitory inhibitor of DNA polymerase alpha and beta. [ 4 ] Inhibition of DNA synthesis through premature concatenation expiration, competitory suppression and the inability of DNA polymerases to adhere adequately to DNA girl strands causes malignant cell programmed cell death.
Drug Discovery:
Cytarabine i.e. Ara-C was derived from cognition gained from the close scrutiny of bioactive Marine nucleosides, found in the marine environment. Cytarabine is an illustration of a marine-derived drug. [ 5 ] The drug was foremost discovered in 1945 by a chemist named Werner Bergmann who collected sponges from the shallow Waterss from Elliot Key, Florida. This unidentified species called Cryptotethia crypta named by Dr. M. W. De Laubenfels discovered more of these sponges off the Islands in the Bahamas. Upon closer scrutiny by the manner of boiling the sponges in propanone in a Soxhlet extractor setup, Bergmann observed crystalline stuff separated from the propanone. This stray stuff was found to be a constituent in a mixture of drugs used for the intervention for acute lymphoblastic leukaemia. UV analysis in the signifier of an soaking up spectrum that was similar to the construction of the nucleotide thymidine. This new compound similar to thymidine was named spongothymidine since the compound was derived from sponges.
This led to the find that a nucleoside has biological activity. The subsequent detonation of compounds and these finds led to the designation of a close parallel, C arabinoside, as powerful antileukemic agent and was later commercialised by Upjohn ( now known as Pharmacia ) as Ara-C. [ 5 ] Other near compounds such as Ara-A were synthesised and commercialised by Burroughs Wellcome ( now GSK ) .
Computer assisted drug design can be used to happen the chief active binding sites. These adhering sites correspondent to deoxycytidine place important bindings to functional groups besides present within DNA in cancerous cells, i.e. the mark enzymes involved in DNA synthesis. Computer assisted drug design allows the drug design to be similar in construction to cytidine i.e. be a cytidine parallel.
Active site volumes of dCKc and dCKm were calculated by bring forthing the adhering pockets of the enzymes. These of which are similar to the construction of Ara-C: [ 6 ]
Drug Synthesis: [ 7 ]
It is possible to synthesize cytarabine, ara-C utilizing the undermentioned synthesis path. This path is besides used and established for the synthesis of ara-AC, an ara-C derived function. This derivative contains an excess N heteroatom within the ring. The first measure in the synthesis path involves hydrogenation of the initial compound utilizing H over a palladium accelerator. This is an illustration of a heterogeneous accelerator that provides a surface for the reactant molecules. The reactant is placed in an ethanolic H chloride solution taking to the decrease of the dual bond.
The following phase in the synthesis path is intervention of the 2nd compound at room temperature with bis-trimethylsilyl-trifluoroacetamide ( BFTFA ) in acetonitrile solution produced the pentakis-trimethylsilyl derived function. This is allowed to reflux for several hours until full transition to the last merchandise ara-C is completed. Vaporization of the reaction solution produces syrup where it is boiled in methyl alcohol to take trimethylsilyl groups by solvolysis. Ara-C is so crystallised from the solution as a consequence.
Drug Selectivity, authority and SAR:
Cytarabine chief mark i.e. selectivity is indistinguishable to that of the nucleoside deoxycytidine due to the fact it is a nucleoside parallel. It acts chiefly as a competitory inhibitor to cytidine triphosphate. Ara-C is metabolised in vivo to ara-CTP and competes with CTP during DNA synthesis with Deoxyribonucleic acid polymerases both alpha and beta.
To exercise its cytoxic effects, cytarabine is converted ab initio to the 5′-phosphate via rate restricting phosphorylation catalyzed by deoxycytidine kinase ( dCK ) in tumor cells and so finally to its 5′-triphosphate ara-CTP.
Ara-CTP presumably Acts of the Apostless both by suppressing the binding of 2′-deoxycytidine triphosphate to DNA polymerase and by incorporation into stretching DNA strands, ensuing in faulty ligation or uncomplete synthesis of Deoxyribonucleic acid fragments and finally cell decease programmed cell death. [ 9 ]
Targets of this chemotherapeutic drug besides include adhering sites of the correspondent molecule cytidine.
The authority of the ara-C is nevertheless limited in its public-service corporation as an anti-cancer nucleoside because of hapless intracellular conveyance features. Besides it has a weak activity as a substrate for tumor cell kinases. Therefore the development of drug opposition as a consequence from reduced nucleoside kinase activity as lowered the efficaciousness of this agent.
Tumour cells deficient in dCK ( deoxycytidine kinase ) are extremely immune to cytarabine, so intramolecular bringing of ara-CMP might be expected to besiege opposition in these cells. [ 9 ] Ara-C and similar nucleoside parallels enter cells via specific transporters which are indispensable to ara-C cytotoxicity in human tumor cells. Hence nucleoside transporter lacking cells are extremely immune to cytarabine. Therefore to turn to this job a prodrug of cytarabine is synthesised and used alternatively which can spread passively into cells where it is metabolised into an active signifier, i.e. intracellular activation, and therefore overcomes resistance jobs such as restricting nucleoside transporters.
An illustration of a prodrug is cytarabine phosphoramidate. An in-vitro survey assay on tumor malignant lymphoid cells indicated the drug inhibited cell growing up to 50 % of the control value, where the stock drug was prepared in absolute ethyl alcohol. This process was undertaken in a 72h incubation period where information recorded fitted a sigmoid curve and the consequences were expressed as the IC50. [ 9 ]
Other surveies in vivo conducted on mice with grafted human malignant neoplastic diseases of different types. [ 12 ]
Cytarabine is effectual against malignant neoplastic disease cells within mice B and mice D. It has some authority against malignant neoplastic disease cells C but opposition develops as a consequence and it is uneffective against A.
The structure-activity relationship, i.e. the relationship between the chemical construction of the molecule and its biological activity is the biological responsiveness with G in DNA reproduction, correspondent to cytidine guanine interactions. The SAR constituents of cytarabine are therefore as follows and derived from cytidine. Besides similar in SAR and responsiveness is gemcitabine which works in an tantamount manner to both cytarabine and cytidine but marks lung malignant neoplastic disease, pancreatic malignant neoplastic disease and chest malignant neoplastic disease cells.
An of import portion of ara-C in conformity to its structural activity relationship lies on the phosphorylation as discussed earlier for this compound ; a close analogy is cytidine and similar in construction gemcitabine phosphorylation by dCK. This SAR constituent is on the OH group to bottom left of the O heteratom in the ring, which becomes phosphorylated.
