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Molecular Design And Synthesis
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The field of molecular design and synthesis has a focus on a strong and diverse research that aims at developing new synthetic methodologies and creates new molecules. The molecules and synthetic models have a varying degree of complexity and have diverse functionalities. Organic chemistry, biochemistry, and organ chemistry form the basis for understanding the relationship between the molecular structure and performance. The field of study helps in designing bio-active compounds and materials by combining experimental and computational methods. Molecular design and chemical synthesis have applications in the research topics involving chemistry, biology, and medicine. The paper presents examples of such research areas for the discovery and development of the future chemotherapeutic agents for cancer treatment.
Cancer is among the leading fatal diseases in the world due to the high cost and sophisticated methods used in its treatment. According to the American Cancer Society, the figures of the cancer cases and deaths continue to increase. The current cancer incidence, mortality, and survival statistics and information on cancer symptoms, risk factors, early detection, and treatment show that in 2014, an estimate of 1,665,540 cancer cases was diagnosed. Cancer also recorded 585, 720 cases of death in U.S thereby becoming the second most common cause of death. It accounts for an approximate of 1 of every four deaths (ACS, 2014).
The common methods used in the treatment of cancer include; surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, hyperthermia, and photodynamic therapy among others. Each of the methods has an underlying principle in its use, and the choice depends on the preference and severity of the cancer condition. Despite the significant progress in the development of cancer detection, prevention, surgery, and therapy; there is no cure that has a general acceptance. Chemotherapy and radiation therapy are very common. Chemotherapy uses medicines or drugs in the treatment processes. On the other hand, radiation therapy uses high-energy penetrating particles that damage the cancer cells. The method can also work in conjunction with other methods of treatment.
The major problem that exists in the traditional cancer chemotherapy is the failure of having tumor-specific treatments. Traditional chemotherapy works on the principle that the rapidly increasing cancer cells have the likelihood of dying in the presence of a cytotoxic agent. However, the principle of using the cytotoxic agents has a limited specificity that may lead to systemic toxicity thereby causing side effects. Thus, it is necessary to develop a molecularly specific cancer therapy method. The method finds use in the specific cancers that include the tumor-targeted drug delivery systems (TTDD). The tumor-targeted drug delivery systems act as the “guided molecular missiles” in the fight against cancer. A TTDD system comprises of a tumor recognition moiety and cytotoxic warhead that has a connection through a linker to form a conjugate. Chemotherapy is an applicable method of treating cancer, but the lack of specificity molecules makes it very toxic. The anticancer drugs kill the cancer cells but also destroy the healthy tissues resulting in the toxicity of the underlying system. There is a recent discovery of new generational taxoids that have excellent activity against cancer stem cells from the colon, prostate, and breast cancers. The developments are an addition to the high potency against drug-sensitive and drug resistance cancer cells and tumors. The paper has a discussion of efficient molecular approaches to the design and development of the efficient “guided molecular missiles” for tumor-targeted drug delivery using highly potent taxoids.
New generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells (Botchkina, Zuniga, Das, Wang, Wang, Zhu, Ojima, 2010).
The new generation taxoid SB-T-1214 has significant activity against the 3D colon cancer spheroids enriched with drug-resistant tumorigenic cell populations (CD 133high/ CD 44 high). In addition, the taxoid hinders the expression of a large number of the stem cell-related genes. A majority of the tumors have a population comprising of tumor initiating, or the cancer stem cells (CSCs) that have the responsibility of tumor development, maintenance and resistance to drugs. The study aimed at determining the stem cell related genomic characteristics of floating 3D multicellular spheroids induced by CD 133high/ CD 44 high colon cancer cells. It also had an objective of examining the CSC specific alterations induced by the new generation taxoid SB-T-1214.
The experiment also dealt with evaluating the cytotoxic effects of SB-T-1214 against CSC-enriched colon cancer cells. In the experiment, the SB-T-1214 cytotoxicity was studied against colon cancer spheroids induced by CD 133high/ CD 44 high cells in 3D cultures. The viable cells that survived the treatment regimen lost their ability to form secondary spheroids. It showed that the CSC population was significantly affected. After the placement of the type I collagen surfaces, the cells that survived the drug treatment showed physical abnormalities.
The use of liquid chromatography and high mass accuracy time of flight mass spectrometry is very helpful in the characterization of a particular protein. The process of mass determination is completed in a short time and provides the scientist with the vital information about the protein expression. The method requires minimal sample preparation and can be automated. It is very sensitive and thus provides reliable results. The produced molecules from the study can be efficiently isolated and checked for their purity using the LC-TOF deconvolution approach.
The increasing evidence shows that the effective anticancer drugs should target the specific tumor-initiating cells that are different from the other tumor counterparts. The problem of non-specificity of the traditional chemotherapy methods results in systemic toxicity and eventual side effects. Thus, it is necessary to have a different approach to the underlying problem. The tumor-targeting drug delivery method proposed in the study finds application in specific cancers. The system consists of a tumor identifying moiety and a cytotoxic warhead connected through a linked to form a conjugate.
American Cancer Society (ACS) (2014) Cancer facts and figures,
Botchkina, G. I., Zuniga, E. S., Das, M., Wang, Y., Wang, H., Zhu, S., Ojima, I. (2010). New- generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells: Molecular Cancer, 9, 192. Doi:10.1186/1476-4598-9-192
Galina Botchkina and Iwao Ojima (n.d) Prostate and Colon Cancer Stem Cells as a Target for Anti-Cancer Drug Development
Galina I Botchkina et. al, (2010) New-generation taxoid SB-T-1214 inhibits stem cell-related gene expression in 3D cancer spheroids induced by purified colon tumor-initiating cells, Molecular Cancer 9: 192
Kunjachan, S., Pola, R., Gremse, F., Theek, B., Ehling, J., Moeckel, D., Lammers, T. (2014) Passive vs. Active Tumor Targeting using RGD-and NGR-modified Polymeric Nanomedicines: Nano Letters, 14(2), 972–981 doi: 10.1021/nl404391r
Madaan, K., Kumar, S., Poonia, N., Lather, V., & Pandita, D. (2014) Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues: Journal of Pharmacy & Bioallied Sciences, 6(3), 139–150 doi:10.4103/0975-7406.130965
Methods of cancer treatment,
Serpe, L., Gallicchio, M., Canaparo, R., & Dosio, F. (2014) Targeted treatment of folate receptor-positive platinum-resistant ovarian cancer and companion diagnostics, with specific focus on vintafolide
Stanislav Jaracz, Jin Chen, Larisa V. Kuznetsova, Iwao Ojima (2005) Recent advances in tumor- targeting anticancer drug conjugates Bioorganic and Medicinal Chemistry, Vol 3(17), 5043-5054
Tumor-Targeting Drug Delivery (2014) Ojima Research Group, RBiotinylated Poly(amino)amine (PANAM) Dendrimers as Carriers for Drug Delivery to Ovarian Cancer Cells In Vitro, Anticancer Research 29: 2933-2944
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