JSM Chemistry

SHetA2 – A Mini Review of a Promising Anticancer Drug

Research Article | Open Access

  • 1. Department of Chemistry, Oklahoma State University, USA
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Corresponding Authors
K. Darrell Berlin, Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078 USA

Heteroarotinoids (Hets) are a novel class of heterocycles which contain an aryl ring and a heterocylic ring and which show potential as anticancer drugs [1]. These heteroarotinoids control cell growth, differentiation, and apoptosis of the cancer cells. Heteroarotinoids were originally derived from an arotinoid class related to retinoids by strategically placing a heteroatom (O,N,S) in the molecular framework of a saturated six-membered ring [2- 7]. This modification in the cyclohexyl ring reduced the toxicity of analogs of several the natural retinoids, including all-trans retinoic acid, by 1000-fold and thus showed promising activity against a variety of cancer cells [2-10].Based on structure-activity relationships (SAR), various Hets have been synthesized with several displaying significant anticancer activity [4-10].Further structural modifications led to a related class of compounds known as Flexible Heteroarotinoids (Flex-Hets) in which certain linking groups situated between a saturated heterocyclic ring and an aryl group were altered. It was discovered that by including more flexible urea and thiourea linkers the anticancer activity increased markedly.1 Consequently, the introduction of a thiourea linker not only provided flexibility between the ring systems, but also increased the scope of activity of the drug against a series of cancer cells lines including breast, head-neck, kidneys, lung and certain ovarian cancers [1,3-6,8,9].

Ultimate structural refinement in the Flex-Hets series led to SHetA2 (1, NSC 726289) [the official name is N-(3,4- dihydro-2,2,4,4,-tetramethyl-2H-1-benzothiopyran-6-yl)-N’(4- nitrophenyl)thiourea] which was developed in our laboratory [1]. The structure is comprised of a sulfur-containing heterocylic ring, a thiourea linker, and a 4-nitrophenyl substituent. SHetA2 (1) showed the greatest level of efficacy and potency in the inhibition of various cancer cells lines while retaining a low level or no activity in normal cell cultures [1,10,11]. The differential effect exhibited by SHetA2 on cancer versus normal cells appears to be by direct targeting of the mitochondria and reducing the Bcl2 and Bcl-xl proteins of cancer cells while causing a minimal effect on normal cells [11].Due to this promising anticancer activity in an organotypic model, the National Cancer Institute (NCI) was prompted to accept the drug into the RAPID (Rapid Access to Preventive Intervention Development, NSC 72689) program for preclinical studies as a therapeutic and chemopreventive agent for cancer [12]. The corresponding ester analog 2 has exhibited good activity but is not the subject of this review.

Chemistry synthesis

To date, there have been only two synthetic strategies for the synthesis of SHetA2 (1). The initial method involved a 6-step sequence starting from thiophenol (3) as shown in Scheme 1 [1]. The thiol 3 underwent a Michael addition with mesityl oxide (4) to give ketone 5. Treatment of ketone 5 with excess CH3 MgBr generated the tertiary alcohol 6. Dehydration-cyclization of 6 was accomplished by AlCl3 in CS2 to afford thiochroman 7. Nitration of thiochroman 7 was achieved using HNO3 /Ac2 O to afford the 6-isomer 8 in a modest yield (26%), with several byproducts being formed, including some via oxidation of the sulfur atom. Reduction of the nitro group in 8 occurred with Fe/ AcOH in refluxing EtOH to yield amine 9, a key intermediate in the synthesis of several Flex-Hets. Finally, amine 9 was further reacted with 4-nitroisothiocyanate to produce SHetA2 (1) in a quantitative yield.

Seltzman and coworkers [13], developed an alternative route to overcome the low yield in the nitration step previously cited in the synthesis of SHetA2 (1). 4-Acetamidothiophenol (10) was used as the starting material, instead of thiophenol (3) (Scheme II). Compound 10 underwent 1,4-addition to mesityl oxide (4) to give 11. Treatment of 11 with methyllithium afforded the carbinol 12 in high yield. Cyclization of 12 afforded the intermediate 13 in the presence of AlCl3 in chlorobenzene as solvent. Hydrolysis of the 13 with conc. HCl and basification gave the key intermediate amine 9, which then treated with 4-nitroisothiocyanate offered 1. This synthetic strategy provided two benefits. Primarily it resulted in a five-fold improvement in the yield of the SHetA2 family of anticancer compounds. Secondly, the procedure also demonstrated an approach to overcome the limitation of the Grignard chemistry in the conversion of 5 to 6, which resulted from poor solubility, and the reduced reactivity of the Grignard reagent as compared to its replacement by methyllithium.

Biological Activity of SHetA2 SHetA2

[1, NSC 726189] has displayed strong activity against head and neck cell carcinoma (UMSCC38 human cell lines) [9] ovarian (OVCAR-3 and Caov-3 cultures) [14,15] and kidney cell lines (Caki-1) [9,14,15] via an induction of apoptosis. Moreover, 1 has exhibited very low toxicity and excellent discrimination between malignant and benign cells [1,11]. The genotoxicity battery (bacterial-Ames test), in vitro chromosomal aberration, and in vivo chromosomal aberration (mouse micronucleus) indicated that SHetA2 was not genotoxic [16]. A subchronic 14- day study in rats and dogs did not reveal significant toxicity up to the highest doses examined [16].A 28-day subchronic toxicity study in dogs resulted in no apparent toxicity with a value of 1500 mg/kg/day with No Adverse Event Level (NOAEL) [16]. Oral administration of SHetA2 (1) reduced the growth of ovarian and kidney cancerous xenograft tumors at 10 mg/kg/day and tumors at 10 mg/kg/day and 60/mg/kg/day, respectively [15,11,17]. Consequently, the therapeutic window for administrative safety with SHetA2 (1) can be 25-150 fold above in vivo effective doses. Ovarian cancer is the most deadly of all gynecologic malignancies which is often diagnosed at a late stage [18]. Following surgery, a combination treatment with cis-platin and taxane has often been applied [19]. Thus 1 might improve therapy for ovarian cancer without significant toxicity.

With renal cancer cell lines (Caki-1 and 786-O), along with an immortalized normal kidney cell line and primary cultures of kidney cells (RTC 91696), SHetA2 (1), exhibited the following inhibitory data [15]. The maximum inhibition for growth observed in terms of efficacy was 84.40% ± 3.86% for the Caki-1, 72.00% ± 5.06% for the 786-O, 51.05% ± 7.07% for HK-2 normal, and 36.84% ± 6.80% for RTC 91696 normal cell lines. The corresponding potency values [IC50-concentration required to induce half maximal efficacy] were 4.93 ± μmol/L, 7.55% ± 0.38 μmol/L, 4.50 ± 0.28 μmol/L, and 4.57 ± 0.49 μmol/L, respectively [15]. A lack of DNA mutagenicity was also observed with 1 with controls which included SHetA3 (2) and DMSO (solvent). The positive controls caused revertant mutations, which allowed bacteria TA1535, TA 1537, TA 98, TA 100, and WP2 uvrA to grow in histidine-deficient media. Neither SHetA2 (1) or SHetA3 (2) induced a major increase in revertant colony counts in any of the bacterial strains [15].

Pharmacokinetic studies in mice have been performed on 1 as well as the development of an HPLC/UV method to determine the presence of the agent in plasma [20].Mouse plasma binding protein was found to be 99.3-99.5% at low molar concentrations. Using a two-compartment deconvolution model, oral bioavailability values were found to be 15% at 20 mg/kg and 19% at 60 mg/kg. An internal standard of XK469 (MeXK469) and SHetA2 (1) were isolated from mouse plasma by solid phase extraction. Separation of the analytes was achieved on a C18 column using a mobile phase of acetonitrile and water. Detection by UV was at 341 nm. Dosage via i.v. bolus at 20 mg/kg and oral administration at 20 mg/kg and 60 mg/kg led to linear standard curves between 25 nM and 2500 nM. Coefficients of variation on the data ranged from 11.1% to 1.5%. Recovery was 85.8% for SHetA2 (1) and 80.6% for the standard. Plasma concentrations of ~10 mM were achieved in about 5 min in mice, following an i.v. bolus dose. A mean initial t1/2 of 40 min and a terminal t1/2 of 11.4 h were obtained. Total body clearance was about 1.81 μL/h/kg. At steady state, the volume of distribution (Vdisss) was 20.8 μL/kg. Thus, the data suggest that SHetA2 (1) is a reasonable candidate for further development as a potential anticancer agent. It was noteworthy that the corresponding urea analog of 1 binds plasma proteins [14] even more efficiently than 1 and has yet to be investigated for activity on a broad scale.

The resistance of normal cells to SHetA2 (1) has been attributed to induction of cell cycle arrest and survival pathways that prevent apoptosis in healthy cells. Specific abnormalities in cancer cells set the integration of these survival pathways to default into apoptosis. Data to support this hypothesis comes from the observation that 1 induces G1 cell cycle arrests in cancer and healthy cell cultures through degradation of cyclin D1 and down-stream signaling consequences involving cyclin E, p21, and Rb [21].

Effect of SHetA2 on Renal and Ovarian Cancer

Kidney cancer constitutes approximately ~3% of all human malignancies with a detection rate of 30,000 new cases per year in US and about 20,000/year in the EU [22]. SHetA2 (1) was chosen as a lead compound for kidney cancer due to its high growth inhibition across a series of 60 human tumor cell lines at micromolar concentrations [3,15,16].It was shown that SHetA2 (1) induced apoptosis in the Caki-1 kidney cancer lines through reduction of Bc1-2 protein and induction of PARP-1 and caspase 3 cleavages, whereas normal kidney epithelial cells exhibited resistance [15].SHetA2 (1) regulated kidney cancer cell growth, differentiation and apoptosis through multiple molecular events by downstream of nuclear factor-κB repression and independent of cellular redox regulation.

Ovarian and renal cancers are two of the most lethal cancers due to their poor response to chemotherapy and their ability to develop resistance [3]. According to a statistical study, ovarian cancer is the leading cause of gynecologic cancer leading to mortality in women in the United States [23]. A study of 1 on renal and ovarian cancer cells revealed altered secretion of thrombospondin-4 (TSP-4), vascular endothelial growth factor A (VEGF), and fibroblast growth factor (bFGF) proteins from normal and cancerous ovarian and renal cultures [3]. Thymidine phosphorylase (TP) expression was inhibited in cancer, but not normal cultures. Endothelial tube formations were stimulated by 1 on cancer cells, but not on normal cells, and 1 reduced secretion of this angiogenic activity [24]. SHetA2 (1) directly inhibited endothelial cell tube formation and proliferation through G1 cell cycle arrest, but not apoptosis. Recombinant TP reversed SHetA2 anti-angiogenic activity. Moreover, 1 inhibition of in vivo angiogenesis was observed in Caki-1 renal cancer xenografts. The data suggest that 1 inhibits angiogenesis through alteration of angiogenic factor secretion by cancer cells and through direct effects on endothelial cells

Effect of SHetA2 on Lung Cancer

Recent studies also evaluated the use of SHetA2 (1) as a possible drug to treat lung cancer. SHetA2 (1) effectively inhibits the growth of NSCLC cells both in vitro and in vivo. The data suggest that 1 triggers ER stress and induces CHOP-dependent DR5 expression, leading to caspase 8-dependant apoptosis [25]. SHetA2 (1) is also believed to activate both the intrinsic and extrinsic pathways of the apoptosis by stress initiation or by cross-talk between the extrinsic and intrinsic apoptosis pathway. Further studies revealed the SHetA2 (1) down regulates c-FLIP in human NSCLC cells which in turn causes induction of apoptosis and enhancement of TRAIL induced apoptosis. This result also complemented the finding of Benbrook and coworkers that the DR5-mediated extrinsic apoptotic pathway played a critical role in SHetA2-induced apoptosis in human NSCLC cells [26].

Synthesis of Metabolite of SHetA2

It is significant that the most useful drugs often require an improvement in hydrophilicity which can increase the aqueous solubility. Higher hydrophilicity sometimes correlates with reduce lipid tissue uptake, which typically results in higher levels of drug availability both in blood or plasma concentrations available for delivery to target tumor cells. It is conceivable that major polar metabolites could result in animals. Consequently, it was imperative to determine the nature of the metabolites from SHetA2 (1). The metabolites are illustrated in (Figure 1) as 14-21. The objectives were to study the in vitro metabolism of SHetA2 (1) in rat and human liver microsomes and in vivo metabolism in the mouse [17]. The mass spectral fragmentation of 1 was determined, and the metabolism of 1 in human and rat liver microsomes was investigated using multi-stage LC-MS (MSn ) on an ion-trap mass spectrometer coupled with a photo diode array (PDA) UV detector set at 340 nm. Incubating 1 in human and rat liver microsomes was done with and without the addition of glutathione (GSH) [17]. Separation of 1 and its metabolites was accomplished on a narrow-bore C18 column with a gradient of two eluents: A, 5% acetonitrile, 0.01% TFA and B, 95% acetonitrile, 0.01% TFA. Monitoring of the disappearance of SHetA2 (1) and the formation of its metabolites was performed at various times in human and rat liver microsomes over 1 hour. Following i.v. and p.o. administration of 1 in the mouse at 20 mg/ kg and 40 mg/kg, respectively, both plasma and metabolite levels of SHetA2 (1) were monitored for 18 hour by HPLC-UV. The in vitro studies in the absence of GSH revealed oxidation of the four methyl groups of 1 which were labeled as one mono-, two di-, and one tri-hydroxylated metabolite. In the presence of GSH, the same primary metabolites were detected along with four GSH adducts of 1. In vivo monohydroxylated metabolites were also found in mouse and rat plasma. Two GSH adducts 20 and 21 of 1 were observed in rat liver following bolus i.v. administration of 1 at 40 mg/kg. It is clear that compounds with increased polarity are the major metabolites from SHetA2 (1) in rats and human liver microsomes.

As described above, 7 metabolites were identified from SHetA2 (1) [17]. The preparation of metabolite 15 has been accomplished in a multi-step synthesis along with a potential prodrug 22. Initial screening by the National Cancer Institute indicated that both 15 and the prodrug 22 possessed low activity in all of the tests. Since the oxidative pathway for SHetA2 primarily involves the sulfur-containing ring, especially the attached methyl groups, the activity of SHetA2 (1) may require the hydrophobic germinal dimethyl groups on the ring for maximum utility. Efforts are underway to grow crystals suitable for X-ray analysis of SHetA2 (1) and of one or more metabolites. In addition, searches are being conducted to determine if a specific enzyme is inactivated by 1 and if a crystal can be grown with the agent docked in its binding site. Such structural information will be instructive regarding preferred conformation of the molecule(s) in the solid state and for an improved design for chemotherapeutic agents related to 1.

Synthesis of Metabolite 15 and Prodrug 22 of SHetA2

The metabolite 15 and the prodrug 22 were synthesized in a 14-step linear sequence starting with thiophenol (3) (Scheme III) [27]. Michael addition of 3 with 3-methyl-2-butenoic acid (23) using piperdine as the base gave 3-(phenylthio)-3-butenoic acid (24), which was then subjected to ring closure using polyphosphoric acid to afford 2,2-dimethylthiochroman-4-one (25). Conversion of 25 to the trimethylsilyl cyanohydrin 26, followed by treatment with phosphorus oxychloride in benzene/ pyridine, provided the unsaturated carbonitrile 27. Saturation of the double bond in 27 with sodium borohydride generated 28, which was alkylated with CH3 I and NaH to give 29. Hydrolysis of the nitrile group gave acid 30, which on reduction, afforded the key intermediate alcohol 31.

Acylation of 31 with acetic anhydride and DMAP in methylene chloride gave the corresponding acetate intermediate 32. The reaction of 32 using an HNO3 /Ac2 O produced the nitro ester 33 in a low yield (~20%). Most reactions prior to nitration and after nitration all gave good to excellent yields. The nitration step proceeded poorly since the required conditions oxidized the sulfur and also led to increased yields of the product nitrated at C-8. Reduction of the nitro group in 33 using iron and acetic acid at 115 ο C afforded the amine 34. Saponification of 34 was accomplished to give amino alcohol 35. Treatment of 34 and 35 with 4-nitrophenylisothiocyanate in dry THF generated the products 15 and 22, respectively, in high yields.

Preliminary Docking Studies

A experimental study was conducted with 1 and 15 at Ambit Biosciences Corporation [4215 Sorrento Valley Blvd, San Diego, C 92121] for activity against B-Raf Kinase [27,28].The technique employed was an active-site dependent competition binding assay with an immobilized, active site directed ligand. In the competitive studies, the percent control for 1 was 87% with B-Raf while that of its mutant [B-Raf-V600E] was 77%. Interestingly, 1 with KIT kinase gave Kd values of 820 nM for KIT and 1300 nM for KIT-V559D.

The corresponding Kd values for 15 were 1200 nM and 4100 nM [27]. Although the activity is less for 1 with the kinases examined, compared to standards cited, additional work is needed to ascertain if other kinases will respond to the action of 1.

To assess the activity of 15, molecular docking experiments employed using Glide (version 5.6, Schrodinger suite 2010) [27] and crystal structures of B-Raf (IUWJ.pdb) and KIT (IT46.pdb) were downloaded from the PDB [27,29-31]. Using the crystal structure of KIT (Figure 2) and by comparing the docking ability of the well-known anticancer agent, Imatinib, it was possible to evaluate the interactions of 15 versus Imatinib in the binding pocket. The H-bonding of 15 with two amino acids in the binding pocket of KIT were identical to that involving Imatinib as was true for hydrophobic contacts. Glide docking scores were -11.97 for Imatinib and -8.70 for 15, with a lower score indicating greater binding affinity. Thus, 15 is suggested to have potential as a possible chemotherapeutic agent for select malignancies.

In summary, SHetA2 (1) has exhibited useful pharmaceutical properties, has low toxicity as determined in mice and dogs, can be quantitatively detected in plasma, has a mean t1/2 of about 40 min as observed in mice, and has displayed a significant differential for inducing apoptosis in cancer cells compared to healthy cells [10,11]. Moreover, the agent has shown strong activity against head/neck cancer cells [5,9] ovarian cancer cells [8,14] and kidney cancer cells [15] as discussed. Mechanistic studies to date have revealed that 1 induces an intrinsic apoptosis pathway through induction of mitochondrial swelling and release of cytochrome c, reduction of Bc1-2 levels, exposure to phosphatidyl serine on the cell surface, and activation of caspase 9 and caspase 3 [8,10,11,15]. Normal cells are resistant to these mitochondrial effects and to apoptosis [10]. It is speculated that the overall influence of SHetA2 (1) may be the result of changes in the membrane of cancer cells compared to normal cells. This remains to be defined by experiment. Nevertheless, based on the information gathered to date on agent 1, the chemistry and the biology strongly suggest that SHetA2 (1) should proceed to clinical trials.



Nammalwar B, Berlin KD, Bunce RA (2013) SHetA2 – A Mini Review of a Promising Anticancer Drug. JSM Chem 1(1): 1005.


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Received : 02 Oct 2013
Accepted : 16 Oct 2013
Published : 19 Oct 2013
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Clinical Journal of Heart Diseases
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Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
TEST Journal of Dentistry
ISSN : 1234-5678
Launched : 2014
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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