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. 2021 Jan 15;12(2):202-210.
doi: 10.1021/acsmedchemlett.0c00460. eCollection 2021 Feb 11.

Investigation on the Anticancer Activity of Symmetric and Unsymmetric Cyclic Sulfamides

Jaden Jungho Jun  1   2 , Divya Duscharla  3 , Ramesh Ummanni  3 , Paul R Hanson  2 , Sanjay V Malhotra  4   5
Affiliations

Investigation on the Anticancer Activity of Symmetric and Unsymmetric Cyclic Sulfamides

Jaden Jungho Jun et al. ACS Med Chem Lett. .

Abstract

The sulfamide functional group has been extensively employed in organic synthesis to discover probes and drugs in various applications such as cancer, human immunodeficiency virus (HIV), virus, and diabetes. Herein, we describe the synthesis of 7-membered symmetric and unsymmetric sulfamide compounds and their biological evaluation through the National Cancer Institute (NCI) panel of 60 human tumor cell lines (NCI-60) and the mechanism of action study. The results of a study from the NCI-60 cell line exhibited that many synthesized cyclic sulfamide compounds inhibited breast cancer (MDA-MB-468). The mechanism of action study of a representative compound 18 showed the inhibition of proliferation and apoptosis in A549 lung cancer cells.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Representative examples of biologically active cyclic sulfamides.
Scheme 1
Scheme 1. Synthesis of Cyclic Sulfamide Compounds
SO2Cl2, Et3N, CH2Cl2. Benzyl bromide (BnBr) or benzyl chloride (BnCl), K2CO3, CH3CN. PMBCl, K2CO3, CH3CN. LiAlH4, THF. Swern oxidation or Dess–Martin periodinane. Ph3P+CH3Br–, n-BuLi, THF. Grubbs Cat-II, benzene. OsO4, NMO, H2O/acetone. m-CPBA, CH2Cl2. VCl3(THF)3, CH2Cl2, Zn; PMBCl = p-methoxybenzyl chloride, THF = tetrahydrofuran, m-CPBA = m-chloroperoxybenzoic acid, DIAD = diisopropyl azodicarboxylate, TFA = trifluoroacetic acid, NMO = N-methylmorpholine.
Scheme 2
Scheme 2. Synthesis of C2-Symmetric Cyclic Sulfamide 34
Methyl (S)-2-hydroxy-4-methylpentanoate, PPh3, DIAD, THF. BnCl or BnBr, K2CO3, CH3CN. TFA, CH2Cl2. BnCl or BnBr, K2CO3, CH3CN. LiAlH4, THF. Oxalyl chloride, DMSO, Et3N, CH2Cl2,-78 °C. Ph3P+CH3Br–, n-BuLi, THF. Grubbs Catalyst-II, benzene, reflux.
Figure 2
Figure 2
(A) A549 cells were treated with compound 18 (same as LSC-JHJ-III-128-13) at μM or DMSO. On exposure of A549 cells to 18, the change in morphology of cells was observed. (B) The A549 cell was treated with compound 18 at 10 μM or DMSO. On exposure of A549 cells to compound, 50% growth inhibition is observed after 36 h.
Figure 3
Figure 3
Effect of compound 18 on the anchorage-independent growth of A549 cells. In clonogenic assays, cells were allowed to grow in soft agar containing 18 (0–50 μM) for 9 days to form colonies. (A) Images of the colony-forming assay and (B) number of colonies stained with crystal violet.
Figure 4
Figure 4
Effect of compound 18 (NSC 764190) on migration of the A549 cell. The representative images of the in vitro scratch assay are shown here. After creating scratches of A549 cell monolayers, cells growing in media containing the test compound (0–50 μM) or DMSO vehicle were analyzed with a phase-contrast microscope, and images are presented. Compound 18 inhibited migration of A549 cells.
Figure 5
Figure 5
Senescence induced by compound 18 was quantified using SA-β-gal-staining. SA-β-gal positive cells are indicated with the arrow mark. The number of SA-β-gal positive cells increased with increasing concentration of compound indicating that compound 18 induces senescence of A549 cells.
See this image and copyright information in PMC

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