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THE CORRELATIONS BETWEEN STRUCTURE AND ACTIVITY IN CASE OF RAKICIDINS

Answer:

TITLE: Critical Review Of The Correlations Between Structure And Activity In Case Of Rakicidins And A Comparative Account Of The Chronic Myeloid Leukemia Resistance To Imatinib Along With 4‑Methylester-Rakicidin A.

ABSTRACT:

The abstract presented the background in terms of rakicidin A for inducing death of cell. The author didnot clearly present the study aim and objective. The abstract lacked a clear method and the cell lines used along with treatment for the 14 rakicidin A analogues. A generalized strategy under a highly efficient combinatorial strategy was provided which lacked a descriptive method against the CML cell lines. Thus the study abstract presented a clear relationship and alterations in the relevance to the configurations at different carbon positions. The study abstract clearly revealed the effects of such alterations in terms of reduced levels related to anti-CML activity (Sang et al., 2016).

A significant result was found in terms of the comparativeanalysis used in association with rakicidin A and the 1a which showed 2.8-fold increased potency in comparison to the imatinib-resistant cell line K562/G+. Although it presented a descriptive account in terms of a 100-fold increase in potency in comparison to imatinib.

AIM: To find the correlation between the structure as well as activity in the case of rakicidins. Also, find an analytical technique for decreasing the level of resistance to chronic myeloid leukemiain association with imatinib along with 4‑methylester-Rakicidin A.

INTRODUCTION AND BACKGROUND:

The present study addressed the account of the majority of the patients suffering from chronic myelogenous leukemia and provided a descriptive account of the BCR-ABL oncogene in terms of the Philadelphia chromosome translocation.  It provided clinical significance about the selective BCR-ABL tyrosine kinase inhibitor in correlation with imatinib. Thus, the treatment of the CML patients and the author clearly enlists the criterion for the type of first-line treatment as well as the research uses the examples for primary resistance to imatinib. The criterion for clinical diagnosis is clearly defined but it lacks research of the literature review in the present topic and no author review was provided. It lacks a descriptive account of the evidence for the efficiency of the new drugs as well as the kind of mutants relevantto the resistance in patients.

No novel approaches were defined for overcoming resistance and what past research was done is not clearly defined highly significant research is based on the CML which exhibitedstem cell properties and role in cancer treatment.The study background provides a clear description of the natural product, rakicidin A as well as the use inhypoxia-selective cytotoxicity in solid tumors but no scientific techniques were reported.  The structural account was provided and biological activities of rakicidins are generalized in the context of synthetic as well as medicinal studies.

METHOD:

The study lacks a clear methodology but diagrammaticrepresentations, as well as tables, are presented for the procedure. The synthesis of a chemical compound is shown via diagrammatic and symbolic illustrations. The Retrosynthetic Analysis of Rakicidins is being presented. The systematic scheme for the combinatorial method is being presented as a paralleled previously reported synthesis strategy. But it is being analyzed that this study cannot be replicated by others. They merely described a scientifictermand no clear representation of the samples being obtained and sample preparation. The procedure is being assigned symbols that are a good representation but it lacks major explanation.  There are methods that were established methods and were referred by other previous articles which lacks innovation and authenticity of the methodology section. Various techniques were highlighted suchas western blotting along with Apoptosis Assay.  There were large data sets that lacked analysis and clear depiction and no legend descriptions were accurately described for the experimental procedure

RESULTS:

The results clearly reveal that in imatinib was utilized in form of a positive control. Thus the comparison was made with the rakicidin A was compared directly.  There are many variables utilized in the experiment which increases the reliability of the results such as IC50 values. The results revealed about the chemical compounds used in the experiment about the medium activity levels in comparison to the K562 cells as well as IC50 values in the range of 5.3 μM to 30.9 μM.

It is significant to note that the controls are not efficient and did not provide correct comparisons. Another major variable that was analyzed was the resistance index of the analyzed compound which was 2.1 as compared to the value of the control i.e. 9.1.  Thus, Capsaseshowed significantdownregulation as it was treated for 72 hours along with compound 1a as well as rakicidin A. Also, the comparative analysis about the resistance revealed the low cytotoxic effect (Takeuchi et al., 2011) having CC50 values of 3.0 μM in normal hematopoietic cells as well as 7.5 μM. The Ponatinib which was utilized for the majority of cancer patients presented T315I mutation for the elimination of the mutant which was T315I and showed a value of 21 as the resistance index.

The article has a logical connection in terms of the rationale of why it was conducted for reducing the resistance as well as analyzing the correlation between structure as well as activity.  Also, results revealed significant additional aspects via various treatments (Sang et al., 2014).

The tables and figures lack significant descriptions about legends and data sets which reduce their reliability. The results must be presented in form of tables for various compounds and various variables must be categorized into different columns.

DISCUSSION:

The study results clearly demonstrate that theauthors have missed making a significant correlation betweenstructure and activity. The study results significantly showed that the imatinib resistance is being interpreted by the study data. The authors are not critical about their experiments and donot disclose the limitations and future research. The results also didnot revealthat the authors are not open-minded about the other possibilities, they are just stuck to the analyzed datasets.

The TKI-refractory CML stem cell were present which is a potential limitation to the clinical efficacy relevant to imatinib. Based on the variable values, it is clear that the different type of  structure rakicidin as well as the stem cell activity of anti-CML cells diverges from the study objective. The use of a fourteen rakicidin analogues in form of a library of which was synthesized reveals that the methodology was based on a combinatorial strategy with high efficiency. Thus compounds were analyzed for the anti-CML activity.  The control used has majorly high values which reveal its consistency with the sample being compared and irrelevant study design.

The results reveal that the authorsdid not clearly provide a justification for the reasons for the failure of in vivo activity of the compounds being utilized as compared to the control. Although the results try to illustrate about the preliminary structure−activity relationship in terms of conjugated diene moiety as well as anti-CML activity of rakicidin A (Tsakos et al., 2016).But in actual the results failed to demonstrate the actual relationship. The choice of the compound being utilized i.e. methylester rakicidin A (1a), was not appropriate as there was a difference in activity against the K562/G+ cell line as compared to imatinib.Future research must focus on improving techniques used for 1a has a as it has a different structure as compared to the anti-CML agents thus, future studies must undertake the differential mode of action of 1a relevant to other types of cell lines.

CONCLUSION AND FUTURE DIRECTIONS:

The evidence provided for the correlation of the structure and activity was not appropriate. The study results hold a low level of adherence with the literature review. It was analyzed that the role of the rakicidin A in death of cell is limited to TKI-resistant chronic myelogenous leukemia cells. But the conjugated diene moiety provided significant results about the found rakicidin A has anti-CML activity. There was little information about the configuration at various carbon positions which resulted in terms of measurement of the reduction in anti-CML activity. The preliminary results also demonstrated thedown-regulation in 1a caspase-3 as well as PARP. The correlational analysis clearly provided significant information about the K562 cell inhibitory activity as well as methylester rakicidin A (1a), though the choice of the compound, as well as replicability of results, was very low.

REFERENCES:

Sang, F., Ding, Y., Wang, J., Sun, B., Sun, J., Geng, Y., Zhang, Z., Ding, K., Wu, L.L., Liu, J.W. and Bai, C., 2016. Structure–activity relationship study of rakicidins: Overcoming chronic myeloid leukemia resistance to imatinib with 4-methylester-rakicidin A. Journal of medicinal chemistry59(3), pp.1184-1196.

Sang, F., Li, D., Sun, X., Cao, X., Wang, L., Sun, J., Sun, B., Wu, L., Yang, G., Chu, X. and Wang, J., 2014. Total synthesis and determination of the absolute configuration of rakicidin A. Journal of the American Chemical Society136(44), pp.15787-15791.

Takeuchi, M., Ashihara, E., Yamazaki, Y., Kimura, S., Nakagawa, Y., Tanaka, R., Yao, H., Nagao, R., Hayashi, Y., Hirai, H. and Maekawa, T., 2011. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr‐Abl positive leukemic cells. Cancer science102(3), pp.591-596.

Tsakos, M., Jacobsen, K.M., Yu, W., Villadsen, N.L. and Poulsen, T.B., 2016. The Rakicidin Family of Anticancer Natural Products–Synthetic Strategies towards a New Class of Hypoxia-Selective Cytotoxins. Synlett27(13), pp.1898-1906.

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