Design, synthesis, and biological evaluation of 2-substituted-2,3,4,9-tetrahydrospiro-ß-carboline-3-carboxylic acid derivatives as first-in-class mast cell stabilizers.

Mast cell degranulation plays a momentous role in myriad diseases like asthma, eczema, allergic rhinitis, and conjunctivitis as well as anaphylactic shock; hence, there is an unmet need for developing new mast cells stabilizers. The reported mast cell stabilizers have a heterocyclic moiety and an acidic group. Furthermore, the role of tryptophan in suppression of mast cell activation is established. Hence, we prepared constrained analogs of tryptophan, which are derivatives of 2,3,4,9-tetrahydrospiro-ß-carboline-3-carboxylic acid, and evaluated them for ex vivo inhibition of compound 48/80-induced mast degranulation activity. By comparing IC50 (µM) values with that of the standard drug sodium cromoglycate (IC50 = 0.489 ± 0.003 µM), compounds with bulky groups like heptyl (compound 9; IC50 = 0.389 ± 0.015 µM) and octyl (compound 10; IC50 = 0.354 ± 0.023 µM) were found to be of similar potency as sodium cromoglycate. Furthermore, the polar group-containing compounds like the chloropropyl (compound 16; IC50 = 0.382 ± 0.083 µM) and benzoyl derivative (compound 14; IC50 = 00.469 ± 0.032 µM) were also found to be of similar potency as sodium cromoglycate. This is a seminal study of spiro-ß-carboline mast cell stabilization having a wider scope in mast cell research; yet, the mechanism of action remains elusive.

Targeting mast cells: Uncovering prolific therapeutic role in myriad diseases.

The mast cells are integral part of immune system and they have pleiotropic physiological functions in our body. Any type of abnormal stimuli causes the mast cells receptors to spur the otherwise innocuous mast cells to degranulate and release inflammatory mediators like histamine, cytokines, chemokines and prostaglandins. These mediators are involved in various diseases like allergy, asthma, mastocytosis, cardiovascular disorders, etc. Herein, we describe the receptors involved in degranulation of mast cells and are broadly divided into four categories: G-protein coupled receptors, ligand gated ion channels, immunoreceptors and pattern recognition receptors. Although, activation of pattern recognition receptors do not cause mast cell degranulation, but result in cytokines production. Degranulation itself is a complex process involving cascade of events like membrane fusion events and various proteins like VAMP, Syntaxins, DOCK5, SNAP-23, MARCKS. Furthermore, we described these mast cell receptors antagonists or agonists useful in treatment of myriad diseases. Like, omalizumab anti-IgE antibody is highly effective in asthma, allergic disorders treatment and recently mechanistic insight of IgE uncovered; matrix mettaloprotease inhibitor marimistat is under phase III trial for inflammation, muscular dystrophy diseases; ZPL-389 (H4 receptor antagonist) is in Phase 2a Clinical Trial for atopic dermatitis and psoriasis; JNJ3851868 an oral H4 receptor antagonist is in phase II clinical development for asthma, rheumatoid arthritis. Therefore, research is still in inchoate stage to uncover mast cell biology, mast cell receptors, their therapeutic role in myriad diseases.

Inundation of asthma target research: Untangling asthma riddles.

Asthma is an inveterate inflammatory disorder, delineated by the airway inflammation, bronchial hyperresponsiveness (BHR) and airway wall remodeling. Although, asthma is a vague term, and is recognized as heterogenous entity encompassing different phenotypes. Targeting single mediator or receptor did not prove much clinical significant, as asthma is complex disease involving myriad inflammatory mediators. Asthma may probably involve a large number of different types of molecular and cellular components interacting through complex pathophysiological pathways. This review covers the past, present, and future therapeutic approaches and pathophysiological mechanisms of asthma. Furthermore, review describe importance of targeting several mediators/modulators and receptor antagonists involved in the physiopathology of asthma. Novel targets for asthma research include Galectins, Immunological targets, K + Channels, Kinases and Transcription Factors, Toll-like receptors, Selectins and Transient receptor potential channels. But recent developments in asthma research are very promising, these include Bitter taste receptors (TAS2R) abated airway obstruction in mouse model of asthma and Calcium-sensing receptor obliterate inflammation and in bronchial hyperresponsiveness allergic asthma. All these progresses in asthma targets, and asthma phenotypes exploration are auspicious in untangling of asthma riddles.

Sulfatase inhibitors for recidivist breast cancer treatment: A chemical review.

Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of hormone-dependent cancers, including breast cancer. Therefore, inhibitors of STS are supposed to be potential drugs for the treatment of breast and other steroid-dependent cancers. The present review concentrates on broad chemical classification of steroid sulfatase inhibitors. The inhibitors reviewed are classified into four main categories: Steroid sulfamate based inhibitors; Steroid non-sulfamate based inhibitors; Non-steroidal sulfamate based inhibitors; Non-steroidal non-sulfamate based inhibitors. A succinct overview of current treatment of cancer, estradiol precursors, STS enzyme and its role in breast cancer is herein described.