Alkylating Agents, the Road Less Traversed, Changing Anticancer Therapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Dipanjan Karati ◽  
Kakasaheb Ramoo Mahadik ◽  
Piyush Trivedi ◽  
Dileep Kumar
Keyword(s):  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Health Hazard ◽  
High Reactivity ◽  
Tumour Cells ◽  
International Agency ◽  
The Road ◽  
Design And Synthesis ◽  
Therapeutic Consequences ◽  
Aziridinium Ion

: Cancer is considered one of the gruelling challenges and poses a grave health hazard across the globe. According to the International Agency for Research on Cancer (IARC), new cancer diagnoses increased to 18.1 million in 2018, with 9.6 million deaths, bringing the global cancer rate to 23.6 million by 2030. In 1942, the discovery of nitrogen mustard as an alkylating agent was a tremendous breakthrough in cancer chemotherapy. It acts by binding to the DNA, and creating cross linkages between the two strands, leading to arrest of DNA replication and eventual cell death. Nitrogen lone pairs of ‘nitrogen mustard’ produce an intermediate 'aziridinium ion' at molecular level, which is very reactive towards DNA of tumour cells, resulting in multiple side effects with therapeutic consequences. Owing to its high reactivity and peripheral cytotoxicity, several improvements have been made with structural modifications for the past 75 years to enhance its efficacy and improve the direct transport of drugs to the tumour cells. Alkylating agents were among the first non-hormonal substances proven to be active against malignant cells and also, the most valuable cytotoxic therapies available for the treatment of leukaemia and lymphoma patients. This review focus on the versatile use of alkylating agents and the structure activity relationship (SAR) of each class of these compounds. This could provide an understanding for design and synthesis of new alkylating agents having enhanced target specificity and adequate bioavailability.

Nitrogen Mustards as Alkylating Agents: A Review on Chemistry, Mechanism of Action and Current USFDA Status of Drugs

2019 ◽  
Vol 19 (9) ◽  
pp. 1080-1102 ◽  
Author(s):  
Ghansham S. More ◽  
Asha B. Thomas ◽  
Sohan S. Chitlange ◽  
Rabindra K. Nanda ◽  
Rahul L. Gajbhiye
Keyword(s):  
Side Effects ◽  
Mechanism Of Action ◽  
Anticancer Agents ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Cross Linking ◽  
Nitrogen Mustards ◽  
Information Leaflets ◽  
Anti Cancer ◽  
Approved Drugs

Background & Objective: :Nitrogen mustard derivatives form one of the major classes of anti-cancer agents in USFDA approved drugs list. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with DNA involving cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Hence it is of great interest to explore this class of anticancer alkylating agents.Methods::An exhaustive list of reviews, research articles, patents, books, patient information leaflets, and orange book is presented and the contents related to nitrogen mustard anti-cancer agents have been reviewed. Attempts are made to present synthesis schemes in a simplified manner. The mechanism of action of the drugs and their side effects are also systematically elaborated.Results::This review provides a platform for understanding all aspects of such drugs right from synthesis to their mechanism of action and side effects, and lists USFDA approved ANDA players among alkylating anticancer agents in the current market.Conclusion: :Perusing this article, generic scientists will be able to access literature information in this domain easily to gain insight into the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in the coming future.

scholarly journals GEOPHYSICAL INVESTIGATION OF GROUNDWATER POLLUTION RESULTING FROM LEACHATE FLOW AT IKOTO AND ORU DUMPSITES IN OGUN STATE OF NIGERIA

2020 ◽  
Vol 6 ◽  
pp. 1
Author(s):  
Adetoro Temitope Talabi ◽  
Taiwo Olakunle Roy-Layinde ◽  
Rasaki Kola Odunaike ◽  
Hamid Titilope Oladunjoye ◽  
Aina Opeyemi Adebanjo
Keyword(s):  
Groundwater Pollution ◽  
Health Hazard ◽  
Subsurface Layer ◽  
Groundwater Table ◽  
Electrode Spacing ◽  
Geophysical Investigation ◽  
The Road ◽  
Ogun State ◽  
Electrical Resistivity Survey ◽  
Electrical Sounding

An electrical resistivity survey was carried out to detect the level of groundwater pollution on Oru and Ikoto dumpsites respectively as it was observed that the dumpsites were sited ignoring the environmental and health hazard. The survey was conducted using ABEM model terrameter with schlumberger array for 1-D vertical electrical sounding (VES) of electrode spacing ranging from 0.25m to 4m. Four VES was conducted on each dumpsite with length between 1m to 120m. The data obtained from the field were interpreted using WINRESIST from which the curve types of each study area were identified. On Oru dumpsite, measurement of VES1 was taken on the dumpsite, VES2 was taken 20m away from the dumpsite, VES3 and VES4 were taken across the road serving as control. Here, there is indication of leachate pollution in VES1 (layer 2) and VES2 (layer 3) while VES3 and VES4 are leachate free, but this leachate present in VES1 and VES2 cannot penetrate into the groundwater table because of the stratigraphy of the area.  At Ikoto dumpsite, measurement of VES4 was taken on the dumpsite, VES1 and VES2 were taken 30m away from the dumpsite on both sides, and while VES3 was taken across the Lagos/Ibadan expressway, serving as control. There is indication of leachate pollution in VES4 (layer2) while in VES1, VES2 and VES3 there is no presence of leachate flow. The leachate present in VES4 can infiltrate into the groundwater table through the highly porous and permeable material in the subsurface layer of the location.

scholarly journals Mathematical Modelling of Two-Wheeler Suspension system in a wavy road

2019 ◽  
Vol 8 (11) ◽  
pp. 3630-3635
Keyword(s):  
Ride Comfort ◽  
Health Hazard ◽  
Suspension System ◽  
Vehicle Body ◽  
Continuous Exposure ◽  
Potential Health ◽  
Suspension Spring ◽  
The Road ◽  
Potential Health Hazard ◽  
Two Wheeler

Two wheelers like motorbikes and scooters are one of the major transports in India. In major cities and towns, it is most common private transport as it is fast and easy approach to the destination. But the prolonged drive in the two-wheeler leads to the potential health hazard and musco-skeletal disorder due to continuous exposure to the vibration caused during the ride and force transmitted to the vehicle body due to road irregularities. It is a challenge of automobile engineers to design a promising suspension system to overcome the risk of ride comfort during continuous driving. In this research, two-wheeler suspension system is modelled with a condition of bump and valley in a wavy road. The road surface is assumed to be wavy and the response of new suspension spring with different materials (stainless steel, tungsten and polymeric) along with viscous damper is analyzed and compared. By this analysis, it will be proposed to industry to modify the suspension system to improve its efficiency and reduce force transmitted to the human body to improve the ride comfort

scholarly journals Evaluation of extracorporeal alkylation of red cells as a potential treatment for sickle cell anemia

Blood ◽  
1976 ◽  
Vol 47 (3) ◽  
pp. 481-488 ◽  
Author(s):  
S Charache ◽  
R Dreyer ◽  
I Zimmerman ◽  
CK Hsu
Keyword(s):  
Cell Survival ◽  
Alkylating Agent ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Red Cells ◽  
Red Cell ◽  
Cell Life ◽  
Red Cell Survival ◽  
Toxic Reactions ◽  
Unacceptable Toxicity

Abstract Nitrogen mustard and nor-nitrogen mustard inhibit sickling, but the concentrations required would be associated with unacceptable toxicity if these agents were administered to patients. Red cells could be treated extracorporeally and infused back into donors, if the alkylating agent could be removed or inactivated, if the treatment per se did not significantly shorten red cell survival, and if viable alkylated lymphocytes could be eliminated from the treated blood. To estimate whether these conditions could be met in a clinical trial, red cells from four dogs were alkylated at 6-wk intervals. No toxic reactions were observed, although not all nor-nitrogen mustard was removed by the washing procedure. Red cell survival was shortened to about half that of control cells, using concentrations of alkylating agent which reduce sickling by 50%. Lymphocytes from treated blood could still exclude trypan blue, but could not be shown to circulate after reinfusion into donor dogs. If alkylating agents are used to treat patients' cells, inhibition of sickling may outweigh the shortening of red cell life span induced by the treatment; blood should probably be irradiated before infusion to avoid administration of alkylated and potentially mutated, but viable, lymphocytes.

Point mutations at multiple sites including highly conserved amino acids maintain activity, but render O6-alkylguanine–DNA alkyltransferase insensitive to O6-benzylguanine

2000 ◽  
Vol 347 (2) ◽  
pp. 519-526
Author(s):  
Meng XU-WELLIVER ◽  
Anthony E. PEGG
Keyword(s):  
Alkylating Agents ◽  
Screening Method ◽  
Point Mutations ◽  
Binding Pocket ◽  
Tumour Cells ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Dna Alkyltransferase ◽  
Resistant Mutants ◽  
Conserved Amino Acids

The DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), is inactivated by reaction with the pseudosubstrate, O6-benzylguanine (BG). This inactivation sensitizes tumour cells to chemotherapeutic alkylating agents, and BG is aimed at enhancing cancer treatment in clinical trials. Point mutations in a 24 amino acid sequence likely to form the BG-binding pocket were identified using a screening method designed to identify BG-resistant mutants. It was found that alterations in 21 of these residues were able to render AGT resistant to BG. These included mutations at the highly conserved residues Lys165, Leu168 and Leu169. The two positions at which changes led to the largest increase in resistance to BG were Gly156 and Lys165. Eleven mutants at Gly156 were identified, with increases in resistance ranging from 190-fold (G156V) to 4400-fold (G156P). Two mutants at Lys165 found in the screen (K165S and K165A) showed 620-fold and 100-fold increases in resistance to BG. Two mutants at the Ser159 position (S159I and S159V) were > 80-fold more resistant than wild-type AGT. Eleven active mutants at Leu169 were also resistant to BG, but with lower increases (5-86-fold). Fourteen BG-resistant mutants were found for position Cys150, with 3-26-fold increases in the amount of inhibitor needed to produce a 50% loss of activity in a 30 min incubation. Six BG-resistant mutants at Asn157 were found with increases of 4-13-fold. These results show that many changes can render human AGT resistant to BG without preventing the ability to protect tumour cells from therapeutic alkylating agents.

scholarly journals Clarification of the pH-dependent kinetic behaviour of papain by using reactivity probes and analysis of alkylation and catalysed acylation reactions in terms of multihydronic state models: implications for electrostatics calculations and interpretation of the consequences of site-specific mutations such as Asp-158-Asn and Asp-158-Glu

1993 ◽  
Vol 294 (1) ◽  
pp. 201-210 ◽  
Author(s):  
G W Mellor ◽  
M Patel ◽  
E W Thomas ◽  
K Brocklehurst
Keyword(s):  
Alkylating Agents ◽  
Kinetic Studies ◽  
High Reactivity ◽  
Ion Pair ◽  
Alkaline Media ◽  
Compound I ◽  
Complex Behaviour ◽  
Ph Dependent ◽  
State Models ◽  
Pair State

1. The complex behaviour of papain (EC 3.4.22.2) in acidic media has been investigated by (a) stopped-flow reactivity probe kinetics using 4,4′-dipyrimidyl disulphide (I) and 2,2′-dipyridyl disulphide (II) as thiol-specific time-dependent inhibitors with markedly different susceptibilities to activation by hydronation (protonation) and (b) using the multitasking application program SKETCHER for the rapid evaluation of pH-dependent kinetic data by means of interactive manipulation of calculated curves. 2. The substantially lower basicity of (I) (pKa 0.91) than that of (II) (pKa 2.45) combined with retention of high reactivity permitted the pKa for the formation of the (Cys-25)-S-/(His-159)-Im+H ion-pair state of papain to be determined kinetically as 3.4, a value close to that (3.3) deduced by potentiometric difference titration [Lewis, Johnson and Shafer (1976) Biochemistry 15, 5009-5017] and lower than the value (approx. 4) often reported from pH-dependent kinetic studies. The higher values are now known to arise from inadequate data analysis that does not take account of other overlapping kinetically influential ionizations. 3. Re-evaluation of the extensive sets of pH-kcat/Km data for the hydrolysis of nine substrates by papain reported by Polgár and Halász (1978) (Eur. J. Biochem. 88, 513-521) by making use of SKETCHER, the known pKa value (3.4) from the reaction with compound (I) and two additional kinetically influential pKa values deduced from the reaction with compound (II) now permits the identification of the pH-dependent events in reactions of papain with inhibitors and substrates. 4. A major conclusion is that, whereas in reactions of simple alkylating agents and compound (I) full nucleophilic character of (Cys-25)-S-/(His-159)-Im+H is provided by hydronic dissociation with pKa 3.3-3.4, in catalysis relatively little catalytic competence is produced consequent upon ion-pair formation. Substantial catalytic competence requires further hydronic dissociation with pKa approx. 4, and for cationic substrates further enhancement is produced by hydronic dissociation with pKa approx. 5. 5. The present work, together with the kinetic analysis of reactions of papain in alkaline media reported by Mellor, Thomas, Topham and Brocklehurst [Biochem. J. (1993) 290, 289-296], defines the kinetically influential ionizations of papain as 3.4, 4.0, 5.0, 8.3 and 10.0 of which 3.4 and 8.3 relate to the formation and subsequent dehydronation of the ion-pair state.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Influence of the Brewing Temperature on the Taste of Espresso

2019 ◽  
Author(s):  
Johanna A. Klotz ◽  
Gertrud Winkler ◽  
Dirk W. Lachenmeier
Keyword(s):  
Health Hazard ◽  
International Agency ◽  
Test Methodology ◽  
Triangle Test

Very hot (> 65 °C) beverages such as espresso were evaluated by the International Agency for Research on Cancer (IARC) as probably carcinogenic to humans. For this reason, research into lowering beverage temperature without compromising its quality or taste is important. For espresso, one obvious possibility consists in lowering the brewing temperature. In two sensory trials using ISO 4120:2004 triangle test methodology, brewing temperatures of 80°C vs. 128°C and 80° vs. 93°C were compared. From the tested levels, espresso brewed at the lowest temperature had the highest acceptance. However, most tasters were unable to distinguish between 80°C and 93°C. The results of these pilot experiments proof the possibility to decrease the health hazard of very hot beverages by lower brewing temperatures.

scholarly journals The efficacy and safety of comfrey

2000 ◽  
Vol 3 (4a) ◽  
pp. 501-508 ◽  
Author(s):  
Felix Stickel ◽  
Helmut K Seitz
Keyword(s):  
Western Europe ◽  
Pyrrolizidine Alkaloids ◽  
Alkylating Agents ◽  
Health Hazard ◽  
Treatment Options ◽  
Clinical Signs ◽  
The United States ◽  
Hepatic Veins ◽  
Therapeutic Approaches ◽  
Carcinogenic Potential

AbstractHerbal medication has gathered increasing recognition in recent years with regard to both treatment options and health hazards. Pyrrolizidine alkaloids have been associated with substantial toxicity after their ingestion as tea and in the setting of contaminated cereals have led to endemic outbreaks in Jamaica, India and Afghanistan. In Western Europe, comfrey has been applied for inflammatory disorders such as arthritis, thrombophlebitis and gout and as a treatment for diarrhoea. Only recently was the use of comfrey leaves recognized as a substantial health hazard with hepatic toxicity in humans and carcinogenic potential in rodents. These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine, and their related N-oxides. The mechanisms by which toxicity and mutagenicity are conveyed are still not fully understood, but seem to be mediated through a toxic mechanism related to the biotransformation of alkaloids by hepatic microsomal enzymes. This produces highly reactive pyrroles which act as powerful alkylating agents. The main liver injury caused by comfrey (Symphytum officinale) is veno-occlusive disease, a non-thrombotic obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Patients may present with either acute or chronic clinical signs with portal hypertension, hepatomegaly and abdominal pain as the main features.Therapeutic approaches include avoiding intake and, if hepatic failure is imminent, liver transplantation. In view of the known serious hazards and the ban on distributing comfrey in Germany and Canada, it is difficult to understand why comfrey is still freely available in the United States.

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