Importance of Organophosphorus Compounds in Medicinal Chemistry Field

Organophosphorus chemistry has a crucial role in the field of drug research [1]. As generally well known, the Adenosine Triphosphate (ATP) plays a key role in the energy processes in all living cells of mammals. There are also natural phosphorus containing organic compound, Phosphocitrate (PC), found in mammalian mitochondria, likely produced by cytosolic phosphorylation of citrate, and which has important role in calcium metabolism, e.g. inhibiting hydroxyapatite precipitation in cells [2-4]. Phosphonates are analogs of natural phosphates, having characteristic C-P bond(s) and phosphonic acid moiety (R-PO3H2). These compounds present as analogs of carboxylic acids, amino acids and peptides [5]. An interest related to these compounds has increased tremendously because of their potential as drugs (also pro-drugs). Phosphonate compounds were observed to have e.g. antibacterial, anticancer and antiparasitic activity [6]; they can be used in medical imaging and diagnostics, and they have phosphoantigen properties [7]. Several compounds containing phosphonate group are already in use as antiviral drugs, like for the treatment of hepatitis B virus (Adefovir or its pro-drug Adefovir dipivoxil), cytomegalovirus (Cidofovir) and HIV/AIDS (Tenofovir or its pro-drug Tenofovir disoproxil) (Figure 1) [6,8]. There is also at least one organophosphorus compound, Remdesivir, under investigation for the treatment of COVID-19 [9].

Figure 1: Examples of anti-viral phosphonate drugs in medicinal use.

One very interesting group of organophosphorus compounds are, Bisphosphonates (BPs), which are analogs of natural pyrophosphate formed by hydrolysis of ATP and found in cells [10]. BPs are active drugs in many kinds of bone or calcium metabolism related diseases like osteoporosis and Paget´s disease [10,11]. They can also be used as bone targeting agents. BPs can be classified as non-nitrogen BPs (non-NBPs) and nitrogen containing BPs (NBPs); they are also categorized to different generations. In figure 2, structures of three different kind of BPs are presented: etidronic acid (1st generation, non-NBP), alendronic acid (2nd generation, NBP) and zoledronic acid (3rd generation, NBP) [12]. BPs present rich chemistry and biology. Applications of BPs cover much more than just medicinal chemistry field; and that is because of their very high affinity to almost any metal cations (alkali metal cations are exception because of their oxidation state +1); so they are potential compounds e.g. for removing/adsorbing metals from different kinds of water solutions [13-16]. Metal contaminated waters can be purified using BPs. As we know, pure water is crucial for all life on earth, and it is definitely health issue also.

Figure 2: Examples of bisphosphonate drugs in medicinal use.

When NBPs are used as drugs, they will induce to formation of ATP analogs ApppI and ApppD (Figure 3) in cells. Non-NBPs will be metabolized also in cells but little bit different way to form adenosine monophosphate (AMP) attached to non-NBP used (ATP analogs also) [17]. These ATP analogs have observed to inhibit cell signaling pathways [18]. Nowadays, ATP analogs can be chemically synthesized, so more options for further research are available [18-20].

Figure 3: ATP analogs ApppI and ApppD induced by NBPs.

As a conclusion, it is more than clear that organophosphorus chemistry and compounds are very important in medicinal chemistry field and they offer an extremely fascinating “world”, which is constantly expanding. Organophosphorus compounds can be found in our bodies either as natural compounds (like ATP and PC) or induced by other compounds; and we really still do not know much of their biological functions and possibilities e.g. as drug LEADs.

I want to share my greatest gratitude and dedicate this paper to my grandmother Aino Kuivalainen, who just passed away. I also want to thank chief laboratory technician, Ms Maritta Salminkoski (retired) for her tremendous work in the field of organophosphorus chemistry.

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